Benzenesulfonamide derivatives

ABSTRACT

A novel benzenesulfonamide derivative represented by the formula: &lt;IMAGE&gt;  has an inhibitory activity against phospholipase A2, so that it is effective in the treatment of diseases for which such an activity is efficacious.

This application is a divisional of application Ser. No. 07/768,515,filed on Sep. 26, 1991, now U.S. Pat. No. 5,281,626, the entire contentsof which are hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to a benzenesulfonamide derivative or apharmacologically acceptable salt thereof exhibiting excellent activityas a drug.

BACKGROUND ART

Phospholipase A is an enzyme catalyzing the hydrolysis of the acyllinkage of glycerophospholipid and includes phospholipase A₁ catalyzingthe hydrolysis of 1-ester linkage of glycerophospholipid andphospholipase A₂ catalyzing that of 2-ester linkage thereof. Althoughboth of the phospholipases are widely distributed in the biologicalworld, they have recently been noted from the standpoint of theirconnection to various diseases.

For example, in ischemic diseases such as cardiac infarction, it isbelieved that phospholipase is activated to disintegrate membranephospholipid, giving an increased infarct size. Furthermore, studieshave been made on the connection of the phospholipase to other varioustroubles.

Under these circumstances, various phospholipase A₂ inhibitors have beenproposed from the standpoint that the inhibition of phospholipase,particularly phospholipase A₂ (PLA₂) is effective in the prevention andtreatment of various diseases (see Japanese Patent Laid-Open Nos.255,749/1985, 175,466/1987, 2,968/1988 and 258,854/1988).

The inventors of the present invention have eagerly studied for manyyears on substances which can inhibit phospholipase A₂ to find out thata benzenesulfonamide derivative or a pharmacologically acceptable saltthereof which will be described below exhibits a high inhibitoryactivity against phospholipase A2 and therefore is useful in theprevention and treatment of various diseases, for example, ischemicdiseases such as cardiac infarction. The present invention has beenaccomplished on the basis of this finding.

DISCLOSURE OF INVENTION

The compound of the present invention is a sulfonamide derivativerepresented by the following formula (I) or a pharmacologicallyacceptable salt thereof: ##STR2## wherein a plurality of R¹ groups eachindependently stand for a hydrogen atom, a cyano, nitro or hydroxylgroup, a halogen atom, a lower alkoxy group, an acyloxy group, a grouprepresented by the formula: --SO₂ --R⁸ (wherein R⁸ stands for a loweralkyl group), a heteroaryl or glycyloxy group or a group represented bythe formula: ##STR3## (wherein p is an integer of 1 to 3), and n is aninteger of 1 to 4;

R² stands for a hydrogen atom or a pyridyl group;

R³ stands for a hydrogen atom or a lower alkyl, cyano or pyridyl group;

R⁴ stands for a hydrogen atom or a lower alkyl group;

R⁵ and R⁶ may be the same or different from each other and each standfor a hydrogen atom, a lower alkyl group, a group represented by theformula: --(CH₂)_(q) --A [wherein q is an integer of 1 to 4; and Astands for a hydroxyl group, a group represented by the formula:##STR4## (wherein R⁹ and R¹⁰ may be the same or different from eachother and each stand for a hydrogen atom or a lower alkyl group), agroup represented by the formula: ##STR5## (wherein R¹¹ stands for ahydrogen atom or a lower alkyl group) or a group represented by theformula: ##STR6## wherein s is an integer of 2 to 5)], an unsubstitutedor substituted cycloalkyl group, a bicycloalkyl, tricycloalkyl orazabicycloalkyl group or a group represented by the formula: ##STR7##(wherein g and h are each an integer of 1 to 4; and B stands for a loweralkyl group, a substituted or unsubstituted arylalkyl group or asubstituted or unsubstituted pyridylalkyl group), or alternatively R⁵and R⁶ may be combined together to form a 6- or 7-membered ring whichmay contain a nitrogen or oxygen atom in addition to the nitrogen atomto which R⁵ and R⁶ are bonded, and said 6- or 7-membered ring may besubstituted with a lower alkyl, arylalkyl, cycloalkylalkyl orheteroarylalkyl group;

a plurality of R⁷ groups each independently stand for a hydrogen atom, alower alkyl group, a lower alkoxy group or a halogen atom; and r is aninteger of 1 or 2, provided that when r is 2, the two R⁷ groups may forma ring together with two adjacent carbon atoms constituting the benzenering; and

m is an integer of 1 or 2.

In the above definition of the compound (I) according to the presentinvention, the lower alkyl group defined with respect to R³, R⁴, R⁵, R⁶,R⁷, R¹¹ and B is a straight-chain or branched alkyl group having 1 to 6carbon atoms and examples thereof include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl(amyl),isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl groups. Among thesegroups, methyl, ethyl, propyl and isopropyl groups are desirable, amongwhich methyl group is most desirable.

The lower alkoxy group defined with respect to R¹ and R⁷ is one derivedfrom the above-mentioned lower alkyl group having 1 to 6 carbon atomsand preferable examples thereof include methoxy, ethoxy, n-propoxy,isopropoxy and n-butoxy groups.

The halogen atom defined with respect to R¹ and R⁷ is chlorine, bromine,iodine or fluorine.

The acyloxy group defined with respect to R¹ is a group wherein anoxygen atom is bonded to an acyl group which is a residue of an organicacid such as aliphatic saturated or unsaturated carboxylic acid orcarbocyclic or heterocyclic carboxylic acid, and particular examples ofthe acyl group include lower alkanoyl groups such as formyl, acetyl,propionyl, butyryl, isobutylryl, valeryl, isovaleryl and pivaloylgroups; aroyl groups such as benzoyl, toluoyl and naphthoyl groups; andheteroaroyl groups such as furoyl, nicotinoyl and isonicotinoyl groups.

Among the groups represented by the formula: --SO₂ --R⁸ in thedefinition of R¹, methylsulfonyl group which corresponds to a grouprepresented by the formula wherein R⁸ is a methyl group is mostdesirable.

The heteroaryl group defined with respect to R¹ is a group derived froma heterocycle containing a nitrogen, oxygen or sulfur atom. Particularexamples thereof include pyridyl, furyl and imidazolyl groups, amongwhich imidazolyl group is most desirable.

Among the groups represented by the formula: ##STR8## (wherein s is aninteger of 2 to 5) in the definition of R⁵ and R⁶, a group representedthereby wherein s is 4 or 5 is most desirable.

That is, a group represented by the above formula wherein the grouprepresented by the formula: ##STR9## is one represented by the formula:##STR10## is most desirable.

The unsubstituted cycloalkyl group defined with respect to R⁵ and R⁶includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl and cyclododecyl groups.

The substituted cycloalkyl group is a cycloalkyl group as describedabove which is either substituted with a lower alkyl group such as amethyl group or a halogen atom or condensed with an aromatic ring suchas a benzene ring or a heterocyclic ring such as a pyridine ring atadjacent carbon atoms constituting the cyclcoalkyl group to form acondensed ring group represented by the formula: ##STR11##

The bicycloalkyl or tricycloalkyl group is an aliphatic saturatedhydrocarbon group which is composed only of two or three rings with atleast two carbon atoms being jointly owned by the rings.

Representative examples of the bicycloalkyl group include ##STR12##

The tricycloalkyl group is, for example, an adamantyl group.

The azabicycloalkyl group is a bicycloalkyl group described above inwhich one of the carbon atoms constituting the bicycloalkyl group isreplaced by a nitrogen atom. Examples thereof include ##STR13##

In the formula: ##STR14## in the definition of R⁵ and R⁶, g and h areeach an integer of 1 to 4. Examples of the group represented by theformula include ##STR15##

The substituted or unsubstituted arylalkyl group defined with respect toB is one derived from an aryl group (such as a phenyl or naphthyl group)which may be substituted with a lower alkyl group such as a methyl orethyl group, a halogen atom or a lower alkoxy group such as a methoxygroup and examples thereof include benzyl and phenethyl groups. Further,the substituted or unsubstituted pyridylalkyl group defined with respectthereto is one derived from a pyridyl group which may be substitutedwith a lower alkyl group such as a methyl or ethyl group, a halogen atomor a lower alkoxy group such as a methoxy group. Preferable examples ofthe group represented by the above formula include ##STR16##

Preferable examples of the 6- or 7-membered ring formed by the groups R⁵and R⁶ which may contain a nitrogen or oxygen atom in addition to thenitrogen atom to which the groups are bonded are as follows: ##STR17##

These 6- or 7-membered rings may be each substituted with a B group suchas a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group.The arylalkyl, cycloalkylalkyl and heteroarylalkyl groups are each thesame as that defined above.

Particular examples thereof are as follows: ##STR18##

Among the groups defined with respect to R⁷, a hydrogen atom is mostdesirable, i.e., the benzene ring is most desirably an unsubstitutedone. When r is 2, the two R⁷ groups may form a ring together withadjacent two carbon atoms constituting the benzene ring. Particularexamples of such a ring are as follows: ##STR19##

In the general formula (I), the groups represented by the formula:(R¹)_(n) each independently stand for a hydrogen atom, a cyano, nitro orhydroxyl group, a halogen atom, a lower alkoxy group, an acyloxy group,a group represented by the formula: --SO₂ --R⁸ (wherein R⁸ stands for alower alkyl group), a heteroaryl group a glycyloxy group or a grouprepresented by the formula ##STR20## (wherein p is an integer of 1 to 3)and n is an integer of 1 to 4. The term "each independently" used inthis description means that when n is an integer of 2 to 4, thesubstituents on the benzene ring may be either the same or differentfrom each other.

In other words, the general formula (I) can be replaced by the followingformula (I'): ##STR21## wherein R², R³, m, R⁴, R⁷, R⁵ and R⁶ are each asdefined above; and R^(a), R^(b), R^(c) and R^(d) may be the same ordifferent from each other and each stand for a hydrogen atom, a cyano,nitro or hydroxyl group, a halogen atom, a lower alkoxy group, anacyloxy group, a group represented by the formula: --SO₂ --R⁸ (whereinR⁸ stands for a lower alkyl roup), a heteroaryl group, a glycyloxy groupor a group represented by the formula: ##STR22## (wherein p is aninteger of 1 to 3).

That is, the benzenesulfonamide derivative according to the presentinvention may be mono-, di-, tri- or tetra-substituted with the groupsdescribed above, the groups being either the same or different from eachother. Among these substituted derivatives, preferred ones are thosewherein the benzene ring is monosubstituted with a lower alkylsulfonylgroup such as a methylsulfonyl group or an imidazolyl, cyano or nitrogroup at the p-position (i.e., 4-position) or is di-substituted with twomembers selected from among halogens and a hydroxyl group, for example,3-fluoro-4-hydroxy and 3,4-dihydroxy derivatives.

The pharmacologically acceptable salt according to the present inventionmay be any conventional nontoxic one and examples thereof includeinorganic acid salts such as hydrochloride, hydrobromide, sulfate andphosphate; organic acid salts such as acetate, maleate, tartrate,methanesulfonate, benzenesulfonate and toluenesulfonate; and amino acidsalts such as argininate, aspartate and glutamate.

Further, the derivative according to the present invention may form ametal salt such as sodium, potassium or calcium salt depending upon thesubstituents.

Although the compound of the present invention may be present as ageometrical isomer, cis or trans, because it has a double bond as shownby its structural formula, it is needless to say that the presentinvention includes both of the isomers.

In order to represent more precisely that the present invention includeboth of the cis and trans isomers, the general formula (I) specifyingthe compound of the present invention can be replaced by the followingformula: ##STR23## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, n and m are eachas defined above.

Representative processes for the preparation of the compound accordingto the present invention will now be described.

PREPARATION PROCESS A ##STR24## (in the above reaction scheme, R¹, R²,R³, R⁴, R⁵, R⁶, m and n are each as defined above; Ac stands for anacetyl group; and X stands for a halogen atom) PREPARATION PROCESS B

A compound represented by the general formula (I) wherein at least oneR¹ group is an acetyloxy or methoxy group can be converted into anotherobjective compound (XIV) by the following process: ##STR25## [whereinR^(e) stands for an acetyloxy (OAc) group or an alkoxy group such as amethoxy group; and t and u are each an integer of 1 to 4 with theproviso that they satisfy the relationship: t+u≦4.] ##STR26## (whereinR^(f) O stands for an acyloxy or glycyloxy group)

PREPARATION PROCESS C

A compound represented by the general formula (I) wherein R⁶ is a grouprepresented by the formula: ##STR27## (wherein g and h are each aninteger of 1 to 4) can be prepared also by the following processes:##STR28## (wherein R¹, R², R³, R⁴, R⁵, R⁷, B, g, h, m and n are each asdefined above) ##STR29## (in the above reaction scheme, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R¹², g, h, m and n are each as defined above)

PREPARATION PROCESS D

A compound represented by the general formula (I) wherein R⁵ and R⁶ forma 6- or 7-membered ring which may contain another nitrogen atom inaddition to the nitrogen atom to which R⁵ and R⁶ are bonded and whichmay be substituted can be prepared also by, e.g., the processes whichwill be described below.

A case wherein the ##STR30## group is one represented by the formula:##STR31## (wherein i and j are each an integer of 2 to 3; and B standsfor a hydrogen atom or a substituent described above) will now bedescribed. ##STR32## (in the above reaction scheme, R¹, R², R³, R⁴, B,i, j, m and n are each as defined above) ##STR33## (wherein R¹, R², R³,R⁴, R¹², i, j, m and n are each as defined above)

Step 1

In this step, a ketone or aldehyde (II) which is known in itself or canbe prepared by a known process is converted into a cinnamic acidderivative (III) through Wittig reaction, aldol condensation orKnoevenagel reaction. When the conversion is conducted through Wittigreaction, a compound (II) is reacted with a Wittig reagent such astriethylphosphonoacetate, triethylphosphonocrotonate ortriethylphosphonopropionate generally in an inert solvent such asdimethylformamide, ether, tetrahydrofuran, dioxane, benzene, toluene ordimethyl sulfoxide in the presence of a base such as potassium butoxide,potassium hydroxide, sodium hydroxide, sodium methoxide, sodiumethoxide, sodium hydride or n-butyllithium at a temperature of -78° to150° C. according to a conventional process to give a compound

The compound (III) can be prepared also through aldol condensation orKnoevenagel reaction according to a conventional process.

Step 2

In this step, the compound (III) prepared in Step 1 is converted into acarboxylic acid derivative (IV) through the hydrolysis of an esterlinkage. For example, the hydrolysis is conducted in a dilute aqueoussolution of an alkali or a mineral acid, preferably a mixture comprisinga 0.5 to 3N aqueous solution of sodium hydroxide and ethanol at a ratioof 1:1 or in a 2 to 6N aqueous solution of hydrochloric acid at roomtemperature to refluxing temperature.

Step 3

In this step, the compound (IV) prepared in Step 2 is halogenated intoan acid halide derivative (V). The halogenation is conducted by reactingthe compound (IV) with oxalyl chloride, thionyl chloride, phosphorustrichloride or phosphorus tribromide in an inert solvent such asdichloromethane, chloroform, dichloroethane, benzene or toluene at roomtemperature to refluxing temperature according to a conventionalprocess. When oxalyl chloride is used, it is preferable to usedimethylformamide as a catalyst.

In some cases, the compound (IV) may be converted into other reactivederivative, for example, acid azide, active ester withN-hydroxybenzotriazole or N-hydroxysuccinimide, symmetric acid anhydrideor mixed acid anhydride with alkylcarbonic or p-toluenesulfonic acid.These reactive derivatives may be also used in Step 7.

Step 4

In this step, an acetanilide derivative (VI) which is known in itself orcan been prepared by a known process is sulfochlorinated into a compound(VII). For example, the compound (VI) is reacted with excesschlorosulfonic acid in an inert solvent such as chloroform,dichloroethane, trichloroethane or nitrobenzene or in the absence of anysolvent at room temperature to 100° C. to give a compound (VII).

Step 5

In this step, the sulfonyl chloride derivative (VII) prepared in Step 4is reacted with an amine (VIII) which is known in itself or can beprepared by a known process to prepare a sulfonamide derivative (IX).For example, the objective compound (IX) can be prepared by reacting thederivative (VII) with an amine (VIII) in a solvent such as water,methanol, ethanol, propanol, acetonitrile, tetrahydrofuran, dioxane,dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform,benzene or toluene in the presence of a base such as sodium acetate,sodium hydrogencarbonate, sodium carbonate, triethylamine or pyridine ata temperature of 0° C. to room temperature.

Step 6

In this step, the sulfonamide derivative (IX) prepared in Step 5 isconverted into an aniline derivative (X) through the hydrolysis of theN-acyl group. The hydrolysis is conducted in a dilute aqueous solutionof an alkali or a mineral acid. Preferably, it is conducted in a 2 to 6Naqueous solution of hydrochloric acid or a 0.5 Lo 3N aqueous solution ofsodium hydroxide at 50° C. to refluxing temperature.

Step 7

In this step, an amide derivative (XI) is prepared by the reaction ofthe acid halide or other reactive derivative (V) prepared in Step 3 withthe aniline derivative (X) prepared in Step 6.

In the above reaction, the compounds (V) and (X) are used in equimolaramounts or either of them is used in slight excess. The reaction isconducted in an inorganic solvent inert to the reaction, for examplepyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene,dichloromethane or chloroform. In some cases, the addition of a basesuch as diisopropylamine, triethylamine, pyridine, picoline, lutidine,N,N-dimethylaniline, 4-dimethyaminopyridine, potassium carbonate orsodium hydroxide is effective in making the reaction proceed smoothly.Although the reaction temperature varies depending upon the kind of thereactive derivative and therefore is not particularly limited, thereaction is generally conducted at a temperature of -20° C. to refluxingtemperature to give an objective compound (XI).

Step 8

Among the compounds (XI) prepared in Step 7, a compound (XII) having anacetoxy group as R¹ is converted into a phenol derivative (XIII) in thisstep through the hydrolysis of the acetyl group.

The hydrolysis is conducted according to a conventional process, forexample, either in a solvent such as water, methanol, ethanol, propanol,acetonitrile, tetrahydrofuran or dioxane in the presence of a base suchas lithium hydroxide, sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate or sodium hydrogencarbonate, or in a 0.5to 6N solution of a mineral acid, at a temperature of 0° C. to refluxingtemperature.

Step 9

Among the compounds (XI) prepared in Step 7, a compound (XII) having analkoxy group such as a methoxy group as R¹ is converted into a phenolderivative (XIII) through the dealkylation of the alkoxy group in thisstep.

The dealkylation is conducted according to a conventional process, forexample, in an inert solvent such as dichloromethane, chloroform,dichloroethane or nitrobenzene in the presence of a dealkylating agent,for example, boron halide such as boron tribromide, boron trichloride orboron triiodide or aluminum halide such as aluminum trichloride oraluminum tribromide at 0° C. to refluxing temperature.

Step 10

In this step, the phenol derivative (XIII) prepared in Step 8 or 9 isacylated into a compound (XIV). The acylation is preferably conducted byreacting the phenol derivative (XIII) with an amino acid such asglycine, alanine or valine or a carboxylic acid such as nicotinic acidin an inert solvent such as acetonitrile, tetrahydrofuran, dioxane,ether, benzene, toluene, dichloromethane, chloroform, dimethylformamideor dimethyl sulfoxide in the presence of a condensing agent such asdicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, ethyl chloroformate,diethyl azodicarboxylate or dipyridyl disulfide at a temperature of 0°C. to refluxing temperature.

Step 11

In this step, a sulfonamide derivative (XVI) is prepared by reacting thesulfonyl chloride derivative (VII) prepared in Step 4 with an aminederivative (XV) wherein R¹² is a nitrogen-protective group such as abenzyl, methoxybenzyl, t-butoxycarbonyl or benzyloxycarbonyl group whichis known in itself or can be prepared by a known process. This reactionmay be conducted in a similar manner to that described in Step 5.

Step 12

In this step, the compound (XVI) prepared in Step 11 is freed from theN-protective group to give an amine derivative (XVII).

When R¹² is a benzyl, methoxybenzyl or benzyloxycarbonyl group, it canbe removed according to a conventional process. For example, it can beremoved by hydrogenating the compound (XVI) in a solvent such as water,methanol, ethanol, propanol, acetonitrile, dioxane, tetrahydrofuran,ether, ethyl acetate or dimethylformamide in the presence of a catalystsuch as palladium/carbon, palladium black, platinum oxide or Raneynickel at room temperature to refluxing temperature. In some cases, thecoexistence of an acid such as acetic or hydrochloric acid ispreferable. When R¹² is a t-butoxycarbonyl group, it can be removed bytreating the compound (XVI) in a 1 to 3N solution of hydrochloric acidin a solvent such as water, methanol or ethanol at a temperature of 0°C. to room temperature or by reacting the compound (XVI) with a fluoridereagent such as KF or tetraalkylammonium fluoride in a solvent such asmethanol, ethanol, acetonitrile, tetrahydrofuran, dioxane ordichloromethane at a temperature of 0° C. to room temperature, though itcan be removed also by a conventional process as described above.

Step 13

In this step, the amine derivative (XVII) prepared in Step 12 isconverted into a compound (XX) through N-alkylation. The alkylation isconducted by a conventional process. For example, when the alkylatingagent is a compound (XVIII), the compound (XX) can be prepared byreacting the compound (XVII) with the compound (XVIII) in a solvent, forexample, dimethylformamide, dimethyl sulfoxide, a lower alkyl alcoholsuch as methanol, ethanol or propanol, acetone, benzene, chloroform ordichloromethane in the presence of a base at room temperature torefluxing temperature. The base includes potassium carbonate, sodiumcarbonate, sodium hydrogencarbonate, sodium methoxide, sodium ethoxideand sodium hydride. In some cases, the additional use of lithium bromideor potassium iodide gives better results.

When the alkylating agent is a compound (XIX), the objective compound(XX) can be prepared by reacting the compound (XIX) with the aminederivative (XVII) in a polar solvent such as water, methanol, ethanol,dioxane tetrahydrofuran or acetonitrile or a mixture thereof with waterin the presence of a small amount of hydrochloric acid, acetic acid orsodium acetate at a temperature of 50° C. to refluxing temperature.

When B is a substituted or unsubstituted pyridylalkyl group, thecompound (XX) can be prepared by the condensation of the compound (XVII)with an alkylating agent represented by the formula (XVIII): B--Z.Particularly, when B is a substituted or unsubstituted pyridylethylgroup (i.e., when the alkyl group in the above definition is an ethylgroup), the compound (XX) can be prepared also by the addition reactionof the compound (XVII) with a compound represented by the formula (XIX)E--CH═CH₂.

When E is a pyridyl group which is unsubstituted or substituted with alower alkyl group, the formula (XIX) can be replaced by the followingformula: ##STR34##

Step 14

In this step, the compound (XX) prepared in Step 13 is converted into ananiline derivative (XXI) through the hydrolysis of the N-acyl group. Thehydrolysis can be conducted in a similar manner to that of Step 6.

Step 15

In this step, an amide derivative (XXII) is prepared by reacting theaniline derivative (XXI) prepared in Step 14 with the acid halide orother reactive derivative (V) prepared in Step 3. This reaction can beconducted in a similar manner to that of Step 7.

Steps 16 to 24

These steps can be each conducted in a similar manner to that describedin one of the above-mentioned steps. The steps corresponding to themrespectively are as follows:

(Step 16→Step 12)

(Step 17→Step 13)

(Step 18→Step 5)

(Step 19→Step 12)

(Step 20→Step 13)

(Step 21→Step 6)

(Step 22→Step 7)

(Step 23→Step 12)

(Step 24→Step 13)

Representative compounds of the present invention will now be describedin order to facilitate the understanding of the present invention,though it is needless to say that the present invention is not limitedby them. They are all represented in free forms.

1.N-[1-(2-phenylethyl)-4-piperidyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

2.N-(1-benzyl-4-piperidyl)-4-{N-methyl-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

3.N-methyl-N-[2-(6-methyl-2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

4.(±)N-[1-(2-pyridylmethyl)-3-hexamethyleneimino]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

5.(E)-N-methyl-N-{4-[4-(2-phenylethyl)homopiperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide,

6.(±)-[1-benzyl-3-hexamethyleneimino]-4-{N-methyl-N-[(E)-N-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

7.N-[1-(2-methylpiopyl)-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

8.N-[1-methyl-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

9. N-(3-quinuclidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

10.N-[3-(N,N-dimethylamino)propyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

11.N-pycloheptyl-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

12. N-[2-(6-methyl-2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2 -propenoyl]amino}benzenesulfonamide,

13.N-[3-(4-pyridyl)propyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

14. N-methyl-N-[2-(2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

15. N-[2-(2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

16.N-(2-pyridylmethyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzensulfonamide,

17.(E)-N-methyl-N-[4-(4-cyclohexylmethyl-1-homopiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide,

18. (E)-N-methyl-N-[4-(4-benzyl-1-homopiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide,

19.(E)-N-methyl-N-{4-[4-(2-phenylethyl)piperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide,

20.(E)-N-methyl-N-{4-[4-(3-pyridylmethyl)piperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenapide,

21.(E)-N-methyl-N-[4-(4-benzylpiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide,

22.N-cycloheptyl-4-{N-methyl-N-[(E)-3-(4-cyanophenyl)-2-propenoyl]amino}benzenesulfonamide,

23.N-(1-benzyl-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-cyanophenyl)-2-propenoyl]amino}benzenesulfonamide,

24.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,

25.N-[1-(1,2,3,4-tetrahydro)naphthyl]-4-{N-methyl-N-[(E)-3-(4-(1-imidazoyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,

26. N-cycloheptyl-4-{N-methyl-N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,

27.N-cyclooctyl-4-{N-methyl-N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,

28.(±)-N-(exo-2-norbornyl)-4-{N-methyl-N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,

29.(±)-N-(endo-2-norbornyl)-4-{N-methyl-N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,

30.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-[4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,

31.N-cyclohexyl-N-methyl-4-{N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,

32.N-cyclohexyl-4-{N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,

33.N-cyclohexyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,

34.N-cyclohexyl-N-methyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,

35.N-cycloheptyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,

36. N-cycloheptyl-4-{N-methyl-N-[(2E,4E)-5-(4-nitrophenyl)-2,4-pentadienoyl]amino}benzenesulfonamide,

37.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

38.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

39.4-{(E)-1-[N-methyl-N-[4-(2-indanyl)aminosulfonylphenyl]amino]-3-propenoyl}phenoxyaceticacid,

40. N-cyclobutyl-4-{N-methyl-N-I(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

41. N-cycloheptyl-4-{N-methyl-N-[(2E,4E)-5-(3,5-dibromo-4-hydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide,

42.N-cycloheptyl-4-{N-methyl-N-[(E)-3-(4-fluorophenyl)-2-propenoyl]amino}benzenesulfonamide,

43.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

44. N-(2-indanyl)-4-{N-methyl-N-[(2E,4E)-5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide,

45.N-[2-(1,2,3,4-tetrahydro)naphthyl]-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

46. N-[2-(1,2,3,4-tetrahydro)naphthyl]-4-{N-methyl-N-[(2E,4E)-5-(3,4-hydroxyphenyl)-2,4-pentadienyl]amino}benzenesulfonamide,

47.N-cycloheptyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

48. N-cycloheptyl-4-{N-methyl-N-[(2E,4E)-5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide,

49.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(2-chloro-3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

50.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3-chloro-3,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

51.N-(2-indanyl)-4-{N-methyl-N-{(E)-3-(2-chloro-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

52.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3-bromo-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

53.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(2-bromo-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

54.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-methyl-2-propenoyl]amino}benzenesulfonamide,

55.N-cyclopentyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

56.N-cyclohexyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

57.N-(1-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

58. N-[2-(2-pyridyl)ethyl-4-{N-methyl-N-[3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

59.N-(2-thiazolyl)-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

60.N-[2-(4,6-dimethyl)pyrimidyl]-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

61.N-(2-(hydroxyethyl)-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

62.N-cyclohexyl-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

63.4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

64.4-{N-isopropyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

65.N-[2-(N,N-dimethylamino)ethyl]-4-(N-methyl-N-[(E)-3-(3.4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

66.N-methyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

67. N-isopropyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

b 68.(E)-N-methyl-N-[4-(4-morpholinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide,

69.4-{N-(E)-3-(3,4-dimethoxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

70.4-{N-(Z)-3-(3,4-dimethoxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,

71.4-{N-(E)-3-(3,4-dimethoxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,

72.4-{N-(Z)-3-(3,4-dihydroxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,

73.4-{N-(E)-3-(3,4-dihydroxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,

74.4-{N-(Z)-3-(3,4-dihydroxyphenyl)-2-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,

75.4-{N-(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

76. N-[4-(1-piperidylmethyl)benzyl]-4-{N-methyl-N-(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

77.N-[1-(2-(3,4-dimethoxyphenyl)ethyl]-4-piperidyl]-4-{N-methyl-N-(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

78.N-[1-(2-(3-pyridyl)ethyl]-4-piperidyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

79.N-[1-(2-(6-methyl-2-pyridyl)ethyl]-4-piperidyl-4-{N-methyl-N-(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

80. N-[4-(1-pyrrolidylmethyl)benzyl]-4-{N-methyl-N-(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

81.N-[8-(5,6,7,8-tetrahydro)quinolyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,

82.N-cyclohexyl-4-{N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

83.N-cyclohexyl-4-methyl-4-{N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

84.N-cycloheptyl-4-{N-methyl-N-[(E)-3-(4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

85.N-cyclooctyl-4-{N-methyl-N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

86.N-cycloheptyl-4-{N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,

87.4-{N-[(E)-3-(3-acetoxy-4-methoxyphenyl]-2-propenoyl]amino}benzenesulfonamide,

88. N-cycloheptyl-4-{N-[(E)-3-([3,4-dihydroxyphenyl]-2-methyl-2-propenoyl]amino}benzenesulfonamide,

89.N-cyclohexyl-4-{N-methyl-N-[(E)-3-([3,5-dihydroxyphenyl]-2-propenoyl]amino}benzenesulfonamide,

90.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-[4-hydroxy-3-methoxyphenyl)-2-cyano-2-propenoyl]amino}benzenesulfonamide,

91.4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}-5,6,7,8-tetrahydro-1-naphthalenesulfonamide,

92.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-[3,4-diglycyloxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

93.N-isopropyl-4-{N-methyl-N-[(E)-3-(2-chloro-3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

94.4-{N-[(E)-3-(2-bromo-4,5-dihdyroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,

95.N-(2-thiazolyl)-4-{N-[(Z)-3-(3,4-dimethoxyphenyl)-2-(3-pyridyl-2-propenoyl]amino}benzenesulfonamide,

96.4-{N-[(Z)-3-(3,4-dimethoxyphenyl)-2-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,

97.N-(thiazolyl)-4-{N-[(E)-3-(3,4-dimethoxyphenyl-2-propenoyl]amino}benzenesulfonamide,

98. 4-{N-[(E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoyl]amino}benzenesulfonamide, and

99.N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-diacetoxyphenyl)-2-propenoyl]amino}benzenesulfonamide.

Pharmacological Experiment Examples with respect to representativecompounds according to the present invention will now be described inorder to illustrate the effects of the present invention in more detail.

PHARMACOLOGICAL EXPERIMENT EXAMPLES

A. Inhibitory activity against phospholipase A₂ (PLA₂) contained in themembrane fraction of rabbit heart or the supernatant fraction thereof

Method

1. Preparation of membrane fraction of rabbit heart and supernatantfraction thereof

An NZW male rabbit was anesthetized by the intravenous administration ofpentobarbital sodium to take out its heart. This heart was washed withice-cooled physiological saline to recover a ventricle, followed by theaddition of ice-cooled 0.25 M sucrose/20 mM tris hydrochloride buffer(pH: 8.0) in an amount of 5 ml per g of the ventricle. The obtainedmixture was mashed with a homogenizer in ice water for 30 minutes andcentrifuged at 1,000 g for 10 min. The supernatant was furthercentrifuged at 105,000 g for 60 min. The centrifugation was conducted at0° to 4° C. The obtained supernatant was used as such as the supernatantfraction for examination. The precipitate was suspended in the samebuffer as that described above and used as the membrane fraction forexamination. The protein concentrations of these fractions were eachadjusted to 5 mg/ml as determined by Lowry method.

2. Determination of PLA₂ -inhibitory activity

A 100 mM CaCl₂ solution was added to the above membrane fraction in anamount of 100 μl per 10 ml of the fraction, while a 100 mM solution ofethylene glycol bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid(EGTA) was added to the above supernatant fraction in an amount of 500μl per 10 ml of the fraction. The obtained mixtures were each pouredinto test tubes in an amount of 0.2 ml per tube, followed by theaddition of 2 μl of a solution of a test compound in dimethyl sulfoxide(DMSO) into each of the tubes, while 2 μl of DMSO was poured into a testtube for control. 5 μl of an 8 mM ethanol solution ofphosphatidylcholine (1-palmitoyl-2-[1-¹⁴ C]arachidonyl, 1.184 MBq/ml)was added to each of the test tubes. The test tubes of the membranefraction were kept at 37° C. for 30 minutes for incubation, while thoseof the supernatant fraction were kept at 37° C. for 5 minutes forincubation. Each incubation was stopped by the addition of 1 ml of Dolereagent. The ¹⁴ C-arachidonic acid was extracted with heptane and theheptane layer was passed through silica gel to remove thephosphatidylcholine contained therein by adsorption. The amount of ¹⁴ Cwas determined with a liquid scintillation counter.

Mepacrine was selected as a comparative compound.

Results

The results are given in Table 1.

                  TABLE 1                                                         ______________________________________                                                    PLA.sub.2 -inhibitory activity IC.sub.30 (μM)                  Compound      membrane   supernatant                                          (Example No.) fraction   fraction                                             ______________________________________                                         2            4.48         40                                                  3            2.4        nt                                                    4            0.032      >100                                                  5            0.007        49                                                  6            0.056      >100                                                  7            0.018      >100                                                  8            0.029      >100                                                  9            0.015        61                                                 14            0.016       >30                                                 15            0.081        61                                                 18            0.18       >100                                                 20            0.045        92                                                 21            0.055      >100                                                 22            0.050      >100                                                 25            0.16         68                                                 26            0.24         59                                                 29            0.45         90                                                 30            0.66       >100                                                 31            0.42         29                                                 38            0.12         29                                                 41            0.98         46                                                 43            3.49         62                                                 44            5.1          39                                                 48            1.7          32                                                 49            1.8          56                                                 50            1.05         38                                                 58            1.5          64                                                 65            16         nt                                                   72            41         nt                                                   77            20         >100                                                 79            0.03       >100                                                 81            0.044      >100                                                 86            0.62         46                                                 87            2.1        nt                                                   mepacrine     >100       >100                                                 ______________________________________                                    

B. Influence on the cardiac infarct size of rat

Sixty-one male rats (weight: 220 to 300 g) were made to get myocardialischemia by the ligation of the coronary artery. After 3 hours from theligation, hearts were taken out of the rats and cut into round slices toobtain preparations. These preparations were stained with myoglobin. Thearea unstained therewith was regarded as a cardiac infarction nidus andthe area ratio of the nidus to the left ventricle was determined by theimage analysis and regarded as the cardiac infarct size.

The cardiac infarct size was reduced as compared with that of thecontrol rat by 21% or 20% by the administration of the compound ofExample 4 or 6 through the tail vein in a dose of 1 mg/kg before 15minutes prior to the ligation of the coronary artery.

C. Toxicity test

A small amount of 1N HCl was added to each of the compounds of Examples4, 6, 7, 8 and 15 to form aqueous solutions. These solutions were eachintravenously administered to the groups of three male SD rats of 7weeks of age in a dose of 50 mg/kg. All of the groups of rats wereobserved for 3 hours after the administration. No rat died.

It can be understood from the results of the above PharmacologicalExperiment Examples that each of the compounds of the present inventionhas a remarkably high inhibitory activity against phospholipase A₂ toarrest the course of a series of ischemic cell diseases which arethought to be caused by the activation of phospholipase A₂, for example,cardiac infarction.

Particularly, the phospholipase A₂ -inhibitory activity of each of thecompounds according to the present invention is remarkably higher thanthat of mepacrine used as a comparative compound.

Accordingly, the compounds of the present invention are useful as aremedy or preventive for various diseases for which the phospholipase A₂-inhibitory action is efficacious.

Particularly, the compounds of the present invention are usable as aremedy for various heart diseases, an antithrombotic drug or the like.

More particularly, the compounds of the present invention are effectivein the treatment and prevention of cardiac infarction; angina pectoris;coogestive cardiac insufficiency accompanied with edema, pulmonarycongestion, hepatomegaly or the like; cerebrovascular diseases such asTIA (transient ischemic attack), cerebral infarction (thrombosis andembolism) or (brain edema, cerebrovascular spasm) cerebralarteriosclerosis; postoperative thrombosis and embolism and bloodstreamdisturbance attendant on the operation of the vessel or theextracorporeal circulation of blood; Buerger disease; and peripheralbloodstream disturbance due to the obliteration and stenosis ofappendicular arteries, for example, arteriosclerosis obliterans, SLE orwhile finger disease, the prevention of relapse of these diseases andthe improvement of prognosis thereof.

Further, the compounds of the present invention are efficacious fordiseases caused by metabolism intermediates of the arachidonic acidliberated by the action of phospholipase A₂, for example, thromboxanessuch as thromboxane A₂, prostaglandins or leukotrienes, while thediseases include inflammatory disease, rheumatoid arthritis andallergoses such as asthma and atopic dermatitis.

Particularly among these diseases, the compounds of the presentinvention are thought to be able to arrest the course of a series ofischemic cell diseases caused by the activation of phospholipase A₂. Thecompounds of the present invention are highly valuable in this sense.

When the compounds of the present invention are used as drugs, they maybe each administered orally or parenterally (as injection, suppositoryor external preparation). Although the dose thereof varies dependingupon the symptom, age, sex, weight and sensitivity of a patient; themethod, timing and interval of administration; the properties,dispensing and kind of preparation; and the kind of an active ingredientand is not particularly limited, the does thereof per adult a day isabout 0.1 to 2,000 mg, desirably about 1 to 1,000 mg, more desirablyabout 5 to 500 mg, most desirably about 20 to 100 mg, which may begenerally administered in 1 to 4 portions a day.

A solid preparation for oral administration according to the presentinvention is prepared by adding a filler and, if necessary, a binder,disintegrator, lubricant, color and/or corrigent to an active ingredientand shaping the obtained mixture into a tablet, coated tablet, granule,powder or capsule.

Examples of the filler include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide; those of the binderinclude polyvinyl alcohol, polyvinyl ether, ethylcellblose,methylcellulose, acacia, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin; those of the lubricant include magnesium stearate,talc, polyethylene glycol, silica and hardened vegetable oil; those ofthe color include those authorized as pharmaceutical additives; andthose of the corrigent include cocoa powder, mentha, herb, aromaticpowder, mentha oil, borncol and powdered cinnamon bark. Of course, thetablet and granule may be suitably coated with sugar, gelatin or thelike, if necessary.

An injection according to the present invention is prepared by adding apH modifier, buffer, suspending agent, solubilizing agent, stabilizer,tonicity agent and/or preservative to an active ingredient at need andconverting the mixture into an injection for intravenous, subcutaneousor intramuscular administration, or administration into coronaryarteries by a conventional process. If necessary, the injection may befreeze-dried according to a conventional method.

Examples of the suspending agent include methylcellulose, Polysorbate80, hydroxyethylcellulose, acacia, tragacanth powder,carboxymethylcellulose sodium and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizing agent include polyoxyethylene hardenedcastor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitanmonolaurate, Macrogol and ethyl ester of castor oil fatty acid.

Further, examples of the stabilizer include sodium sulfite, sodiummetasulfite and ether and those of the preservative include methylp-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresoland chlorocresol.

EXAMPLE

Examples of the present invention will now be described below, though itis needless to say that the present invention is not limited to them.The preparation of the starting compounds for preparing the compounds ofthe present invention will be described in the following PreparativeExamples preceding Examples.

PREPARATIVE EXAMPLE 1 4-(Methylthio)benzaldehyde dimethyl acetal##STR35##

A suspension of K-10 (32 g) in trimethyl orthoformate (115 ml, 1.05 mol)was added to a solution of 4-(methylthio)benzaldehyde (31.0 g, 0.203mol) in dichloromethane (300 ml) at 0° C. The obtained mixture wasstirred at room temperature for 20 minutes and filtered to remove theK-10. The filter cake was washed with dichloromethane. The filtrate andwashings were together washed with a saturated aqueous solution ofsodium hydrogencarbonate and a saturated aqueous solution of commonsalt, dried over magnesium sulfate and concentrated in a vacuum to givethe title compound as a pale-yellow oil (39.0 g, 96%).

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.29 (4H, brs), 5.36 (1H, s), 3.26 (6H, s),2.50 (3H, s).

PREPARATIVE EXAMPLE 2 4-(Methylsulfonyl)benzaldehyde dimethyl acetal##STR36##

m-Chloroperbenzoic acid (115.0 g, 0.567 mol) was added to a suspensionof the 4-(methylthio)benzaldehyde dimethyl acetal (50.0 g, 0.252 mol)prepared in Preparative Example 1 and sodium hydrogencarbonate (73.1 g)in dichloromethane (1.00 l) at 0° to 10° C. in portions (over a periodof about one hour and 20 minutes). The obtained suspension was stirredat room temperature for 18 hours and poured into an aqueous solution (1l) of sodium sulfite (100.0 g) under cooling to decompose excessperacid. The resulting solution was extracted with dichloromethane andthe organic layer was washed with a saturated aqueous solution of commonsalt, dried over magnesium sulfate and concentrated in a vacuum. Theobtained solid residue was recrystallized from hexane/isopropylether/ethyl acetate to give the title compound as a colorless crystal(53.9 g, yield: 93%).

m.p. (°C.): 100 to 110

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.92 (2H, d, J=7.9), 7.61 (2H, d, J=7.9),5.50 (1H, s), 3.28 (6H, s), 3.24 (3H, s).

PREPARATIVE EXAMPLE 3 4-Methylsulfonyl)benzaidehyde ##STR37##

1N Hydrochloric acid (200 ml) was added to a solution of the4-(methylsulfonyl)benzaldehyde dimethyl acetal (39.4 g, 0.171 mol)prepared in Preparative Example 2 in dioxane (200 ml). The obtainedmixture was stirred under heating at 100° C. for 20 minutes to conduct areaction. The reaction mixture was cooled by allowing to stand andconcentrated in a vacuum to give a crystal. This crystal was recoveredby filtration, washed with water and dried to give the title compound asa colorless crystal (30.9 g, 98%).

m.p. (°C.): 153 to 157

¹ H-NMR (90 MHz, CDCl₃) δ: 10.10 (1H, s), 8.06 (4H, s), 3.10 (3H, s).

PREPARATIVE EXAMPLE 4 Ethyl (E)-3-(4-methylsulfonyl)phenyl-2-propenoate##STR38##

A solution of ethyl diethylphosphonoacetate (46.2 ml, 0.233 mol) intetrahydrofuran (180 ml) was dropped into a solution of sodium hydride(60% in mineral oil, 9.20 g, 0,230 mol) in tetrahydrofuran (250 ml) at0° C. The obtained solution was stirred at that temperature for 10minutes. A solution of the 4-(methylsulfonyl)benzaldehyde (40.4 g, 0,219mol) prepared in Preparative Example 3 in dimethylformamide (300ml)/tetrahydrofuran (50 ml) was dropped into the resulting solution at0° C. The obtained mixture was stirred at room temperature for 2 hoursand cooled with ice again, followed by the addition of an aqueoussolution (1.0 l) of ammonium chloride (25 g). The obtained mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of common salt, dried over magnesium sulfateand concentrated in a vacuum. The solid residue was recrystallized fromhexane/isopropyl ether to give the title compound as a colorless crystal(48.8 g, yield: 87%).

m.p. (°C.): 91 to 92

¹ H-NMR (90 MHz, CDCl₃) δ: 7.96 (2H, d, J=8.6), 7.70 (1H, d, J=15.8),7.68 (2H, d, J=8.6), 6.54 (1H, d, J=15.8), 4.29 (2H, q, J=7.0), 3.07(3H, s), 1.35 (3H, t, J=7.0).

PREPARATIVE EXAMPLE 5 (E)-3-(4-Methylsulfonyl)phenyl-2-propenoic acid##STR39##

The ethyl (E)-3-(4-methylsulfonyl)phenyl-2-propenoate (48.1 g, 0.189mol) prepared in Preparative Example 4 was suspended in a mixturecomprising ethanol (300 ml) and 1N aqueous sodium hydroxide (300 ml).The obtained suspension was stirred at 50° C. for one hour.

The obtained solution was cooled with ice and 1N hydrochloric acid (330ml) was dropped thereinto to precipitate a crystal. This crystal wasrecovered by filtration, washed with water and isopropyl ether and driedto give the title compound as a colorless crystal (42.4 g, 99%).

m.p. (°C.): 230 to 240

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.95 (4H, s), 7.67 (1H, d, J=15.8), 6.70(1H, d, J=15.8), 3.24 (3H, s).

The same procedure as that of Preparative Example 4 or 5 was repeatedexcept that 3-fluoro-4-methoxybenzaldehyde,3,5-dibromo-4-hydroxybenzaldehyde, 3-(3,4-dimethoxybenzoyl)pyridine or3,4-dimethoxybenzaldehyde was used instead of4-(methylsulfonyl)benzaldehyde or that triethyl-4-phosphonocrotonate ortriethyl-2-phosphonopropionate was used instead oftriethylphosphonoacetate to prepare the compounds listed in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    Prep.                       m.p.                                              Ex. Structural formula      (°C.)                                                                       .sup.1 H-NMR δ                         __________________________________________________________________________         ##STR40##              185-195                                                                             ##STR41##                                   7                                                                                  ##STR42##              201-205                                                                             ##STR43##                                   8                                                                                  ##STR44##              103-131                                                                             ##STR45##                                   9                                                                                  ##STR46##              216-218                                                                             ##STR47##                                   __________________________________________________________________________

PREPARATIVE EXAMPLE 10 Ethyl(Z)-3-{3,4-dimethoxyphenyl)-2-(3-pyridyl)-2-propenoate ##STR48##

n-Butyllithium (1.6M hexane solution, 99.2 ml) was dropped into asolution of diisopropylamine (23.4 ml, 166.6 mmol) in tetrahydrofuran(320 ml). The obtained mixture was stirred at 0° C. for 30 minutes. Asolution of ethyl 3-pyridylacetate (24.0 ml, 158.9 mmol) intetrahydrofuran (20 ml) was dropped into the resulting mixture at -70°C. and the obtained mixture was stirred at 0° C. for 15 minutes. Asolution of 3,4-dimethoxybenzaldehyde (27.6 g, 166.0 mmol) intetrahydrofuran (100 ml) was dropped into the mixture at 0° C. Theobtained mixture was stirred at room temperature overnight, followed bythe addition of water. The obtained mixture was extracted with ether.The organic layer was washed with water and a saturated aqueous solutionof common salt, dried over magnesium sulfate and concentrated. The oilyresidue was purified by flash column chromatography (ethylacetate/hexane=3:2) to give the title compound as a pale yellow oil(18.19 g, yield: 37%).

¹ H-NMR (400 MHz, CDCl₃) δ: 8.58 (1H, brd, J=4.1), 8.50 (1H, brs), 7.88(1H, s), 7.60 (1H, dt, J=7.7, 1.8), 7.33 (1H, dd, J=7.7, 4.9), 6.79 (1H,dd, J=8.5, 2.2), 6.72 (1H, d, J=8.5), 6.41 (1H, d, J=2.2), 4.25 (2H, q,J=7.0), 3.81 and 3.45 (each 3H, s), 1.30 (3H, q, J=7.0).

NOE: 7.88 ↓→6.79 (7.4%), 6.41 (4.2%); 6.41↓→7.88 (4.6%), 3.45 (10.47%).

PREPARATIVE EXAMPLE 11(Z)-3-(3,4-Dimethoxyphenyl)-2(3-pyridyl)-2-propenoic acid ##STR49##

The ethyl (Z)-3-(3,4-dimethoxyphenyl)-2-(3-pyridyl-2-propionate (2.00 g,6.39 mmol) prepared in Preparative Example 10 was dissolved in a mixturecomprising 1N aqueous sodium hydroxide (5 ml) and ethanol (5 ml). Theobtained solution was stirred at room temperature for 5 hours and washedwith ethanol (20 ml). The pH of the obtained aqueous layer was adjustedto about 7 by the addition of 1N aqueous hydrochloric acid (about 5.0ml) to thereby precipitate a crystal. This crystal was recovered byfiltration and washed with water and ether to give the title compound asa white crystal (0.71 g, yield: 39%).

m.p. (°C.): 190 to 191

¹ H-NMR (90 MHz, DMSO₄ -d₆) δ: 8.54 (1H, dd, J=4.8, 1.8), 8.34 (1H, dd,J=1.8, 0.9), 7.81 (1H, s), 7.66 (1H, dt, J=8.0, 1.8), 7.43 (1H, ddd,J=8.1, 4.8, 0.9), 6.86 (1H, d, J=8.8), 6.72 (1H, dd, J=8.8, 1.5), 6.49(1H, d, J=1.5).

PREPARATIVE EXAMPLE 12 4-(N-Acetyl-N-methylamino)benzenesulfonylchloride ##STR50##

N-Methylacetanilide (25.0 g, 188.0 mmol) was added to chlorosulfonicacid (62.8 ml) under cooling with ice in portions at such a rate as notto raise the temperature of the resulting mixture to 50° C. or above,which took about 10 minutes. The obtained mixture was stirred at 80° C.for 2.5 hours and poured into a mixture comprising ice (200 ml), hexane(30 ml) and isopropyl ether (30 ml) under cooling with ice at 20° C. orbelow in portions to decompose excess chlorosulfonic acid. Theprecipitated crystal was recovered by filtration, washed with water anddissolved in ethyl acetate. The obtained solution was washed with waterand a saturated aqueous solution of common salt. The organic layer wasdried over magnesium sulfate and concentrated to give the title compoundas a white crystal (19.4 g, yield: 42%).

m.p. (°C.): 139 to 140

¹ H-NMR (90 MHz, CDCl₃) δ: 8.04 (2H, d, J=9.0), 7.43 (2H, d, J=9.0),3.36 (3H, s), 2.08 (3H, s).

PREPARATIVE EXAMPLE 13 N-Cycloheptyl-4-(N-methylamino)benzenesulfonamide##STR51##

Cycloheptylamine (2.26 ml, 17.8 mmol) was added to a suspension of the4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (4.00 g, 16.2 mmol)prepared in Preparative Example 12 and sodium acetate (3.98 g) inethanol (40 ml). The obtained mixture was stirred at room temperaturefor 4 hours, followed by the addition of water. The obtained mixture wasextracted with ethyl acetate and the organic layer was washed with waterand a saturated aqueous solution of common salt, and dried overmagnesium sulfate.

Ethanol (20 ml) and 1N aqueous sodium hydroxide (20 ml) were added tothe obtained white crystal[N-cycloheptyl-4-(N-acetyl-N-methylamino)benzenesulfonamide] (4.72 g,90%). The obtained mixture was heated under reflux overnight, acidifiedby the addition of 1N aqueous hydrochloric acid and adjusted to pH 8with sodium hydrogencarbonate. The resulting mixture was extracted withethyl acetate and the organic layer was dried over magnesium sulfate andconcentrated to precipitate a crystal. This crystal was recovered byfiltration and washed with ether to give the title compound as a whitecrystal (1.92 g, 44%).

m.p. (°C.): 111 to 113

¹ H-NMR (400 MHz, DMSO-d₆) δ: 7.47 (2H, d, J=8.8), 7.09 (1H, d, J=7.2),6.57 (2H, d, J=8.8), 6.44 (1H, brq, J=4.8), 2.72 (3H, d, J=4.8).

EXAMPLE 14 N-(2-Indanyl)-4-(N-methylamino)benzenesulfonamide ##STR52##

2-Indanylamine hydrochloride (9.68 g, 57.1 mmol) was added to asuspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride(12.84 g, 51.9 mmol) prepared in Preparative Example 12 and sodiumacetate (18.73 g) in ethanol (100 ml). The obtained mixture was stirredat room temperature for 3 hours, followed by the addition of water. Theobtained mixture was extracted with ethyl acetate. The organic layer waswashed with water and a saturated aqueous solution of common salt, driedover magnesium sulfate, and concentrated to giveN-(2-indanyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide as a whitecrystal (16.92 g, 95%). Ethanol (80 ml) and 1N aqueous sodium hydroxide(80 ml) were added to the white crystal. The obtained mixture was heatedunder reflux overnight, acidified with 1N aqueous hydrochloric acid,adjusted to pH 8 with sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was dried over magnesium sulfate andconcentrated to precipitate a crystal. This crystal was recovered byfiltration and washed with ether to give the title compound as a whitecrystal (6.79 g, 46%).

m.p. (°C.): 136 to 137

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.85 (2H, d, J=8.8), 7.53 (2H, d, J=8.8),7.08 (4H, s), 3.90 (1H, m), 3.24 (3H, s), 3.12˜2.54 (4H, m).

PREPARATIVE EXAMPLE 15N-[2-(6-Methyl-2-pyridyl)ethyl]-4-(N-methylamino)benzenesulfonamide##STR53##

N-Methyl-N-[2-(6-methyl-2-pyridyl)ethyl]amine (14.66 g, 97.7 mmol) wasadded to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonylchloride (24.2 g, 97.3 mmol) prepared in Preparative Example 12 andsodium acetate (24.0 g) in ethanol (140 ml). The obtained mixture wasstirred at room temperature overnight, followed by the addition ofwater. The obtained mixture was extracted with ethyl acetate. Theorganic layer was washed with water and a saturated aqueous solution ofcommon salt, dried over magnesium sulfate, and concentrated to giveN-[2-(6-methyl-2-pyridyl)ethyl]-4-(N-acetyl-N-methylamino)benzenesulfonamideas a colorless oil. This oil was dissolved in 4N aqueous hydrochloricacid. The solution was heated under reflux for 2 hours. The pH of themixture was adjusted to about 8 by the addition of an aqueous solutionof sodium hydrogencarbonate. The resulting mixture was extracted withethyl acetate. The organic layer was washed with water and a saturatedaqueous solution of common salt, dried over magnesium sulfate, andconcentrated to give an oily residue. This residue was purified by flashcolumn chromatography (chloroform/methanol/aqueous ammonia=97:3:0.3) togive the title compound as a light brown oil (25.8 g, overall yield oftwo steps: 83%).

¹ H-NMR (400 MHz, CDCl₃) δ: 7.56 (2H, d, J=8.8), 7.49 (1H, t, J=8.0),7.03 (1H, d, J=8.0), 6.98 (1H, d, J=8.0), 6.57 (2H, d, J=8.8), 4.28 (1H,brq, J=5.2), 3.36 (2H, t, J=7.2), 2.99 (2H, t, J=7.2), 2.87 (3H, d,J=5.2), 2.69 (3H, s), 2.50 (3H, s).

PREPARATIVE EXAMPLE 16N-(1-Benzyl-4-piperidyl)-4-(N-methylamino)benzenesulfonamidedihydrochloride ##STR54##

4-Amino-1-benzylpiperidine (3.63 ml, 17.8 mmol) was added to asuspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride(4.00 g, 16.2 mmol) prepared in Preparative Example 12 and sodiumacetate (2.65 g) in ethanol (40 ml). The obtained mixture was stirred atroom temperature for 4 hours, followed by the addition of water. Theobtained mixture was extracted with ethyl acetate. The organic layer waswashed with water and a saturated aqueous solution of common salt, driedover magnesium sulfate, and concentrated to giveN-(1-benzyl-4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide asa colorless viscous oil. This oil was dissolved in 4N aqueoushydrochloric acid and the obtained solution was heated under reflux for3 hours. The resulting mixture was concentrated to give a solid residue.This residue was recrystallized from ethyl acetate to give the titlecompound as a white crystal (highly hygroscopic one) (5.80 g, overallyield of two steps: 80%).

m.p. (°C.): amorphous (highly hygroscopic)

¹ H-NMR (400 MHz, DMSO-d₆) δ: 7.60 (1H, m), 7.54 (2H, m), 7.50 (2H, d,J=8.8), 7.44 (1H, m), 7.42 (2H, m), 6.60 (2H, d, J=8.8), 4.13 (2H, s),3.18 (2H, m), 3.08 (2H, m), 2.87 (2H, m), 2.71 (3H, s), 1.73 (4H, m).

PREPARATIVE EXAMPLE 17N-(4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide acetate##STR55##

N-(1-Benzyl-4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamidewas prepared as a colorless oil from the4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (20.0 g, 80.8 mmol)and 4-amino-1-benzylpiperidine (18.16 ml, 88.9 mmol) in a similar mannerto that described in Preparative Example 16. This oil was dissolved inethanol (200 ml), followed by the addition of glacial acetic acid (10.0ml). The obtained mixture was stirred in the presence of 10%palladium/carbon (water-containing one, 2.00 g) in a hydrogen atmosphere(1 atm) at 50° C. for 5 hours and filtered to remove the catalyst. Thefiltrate was concentrated to precipitate a crystal. The resultingmixture was washed with ethyl acetate and filtered to give the titlecompound as a white crystal (29.70 g, overall yield of two steps: 100%).

m.p.: 177 to 184

¹ H-NMR (400 MHz, DMSO-d₆) δ: 7.84 (2H, d, J=8.8), 7.55 (2H, d, J=8.8),3.22 (3H, s), 3.11 (1H, m), 2.90 (2H, m), 2.47 (2H, m), 1.90 (3H, brs),1.85 (3H, s), 1.57 (2H, m), 1.32 (2H, m).

PREPARATIVE EXAMPLE 18N-[1-(2-Phenylethyl)-4-piperidyl]-4-(N-methylamino)benzenesulfonamidedihydrochloride ##STR56##

The N-(4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide acetate(3.71 g, 10.6 mmol) prepared in Preparative Example 17 was dissolved ina suspension of sodium hydrogencarbonate (2.52 g) and potassium iodide(3.32 g) in dimethylformamide (50 ml), followed by the addition of2-bromoethylbenzene (1.49 ml, 11.0 mmol). The obtained mixture wasstirred at 70° C. for 3 hours, followed by the addition of water. Theobtained mixture was extracted with ethyl acetate. The organic layer waswashed with water and a saturated aqueous solution of common salt, driedover magnesium sulfate, and concentrated to giveN-[1-(2-phenylethyl)-4-piperidyl]-4-(N-acetyl-N-methylamino)benzenesulfonamideas a colorless oil (3.19 g, yield: 77%).

This oil was dissolved in 1N aqueous sodium hydroxide (50 ml). Theobtained solution was heated under reflux for 2 hours and acidified with1N aqueous hydrochloric acid. The pH of the solution was adjusted toabout 8 with an aqueous solution of sodium hydrogencarbonate. Theresulting mixture was extracted with ethyl acetate and the organic layerwas washed with water and a saturated aqueous solution of common salt,dried over magnesium sulfate, and concentrated to give the titlecompound in free form as a colorless oil (2.60 g). This oil wasconverted into a hydrochloride in ethyl acetate-ethanol to give thetitle compound as a white crystal (2.55 g, yield: 74%).

m.p. (°C.): amorphous (hygroscopic)

¹ H-NMR (400 MHz, DMSO-d₆) δ: 7.55 (2H, d, J=8.8), 7.31 (3H, m), 7.22(2H, m), 6.67 (2H, d, J=8.8), 3.45˜3.00 (6H, m), 2.92 (2H, m), 2.72 (3H,s), 1.75 (4H, m).

PREPARATIVE EXAMPLE 19N-{1-[2-(6-Methyl-2-pyridyl)ethyl]-4-piperidyl}-4-(N-methylamino)benzenesulfonamide##STR57##

The N-(4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide acetate(3.71 g, 10.0 mmol), 6-methyl-2-vinylpyridine (1.43 g, 12.0 mmol ) andsodium acetate (0.82 g) were dissolved in a mixture comprising methanol(20 ml) and water (20 ml). The obtained solution was heated under refluxfor 5 hours, followed by the addition of sodium hydroxide (3.20 g). Theobtained mixture was heated under reflux for additional three hours andacidified with 2N aqueous hydrochloric acid. The pH of the mixture wasadjusted to about 8 with an aqueous solution of sodiumhydrogencarbonate. The resulting mixture was extracted with ethylacetate. The organic layer was washed with water and a saturated aqueoussolution of common salt, dried over magnesium sulfate and concentrated.The obtained oily residue was purified by column chromatography(chloroform:methanol:aqueous ammonia=90:9:1) and recrystallized fromethyl acetate/ether to give the title compound as a white crystal (2.71g, overall yield of two steps: 70%).

m.p. (°C.): 80 to 84

¹ H-NMR (400 MHz, DMSO-d₆) δ: 7.53 (1H, t, J=8.0), 7.49 (2H, d, J=8.8),7.20 (2H, d, J=7.2), 7.01 (2H, d, J=8.0), 6.58 (2H, d, J=8.8), 6.47 (1H,brq, J=5.2), 2.75 (6H, m), 2.72 (3H, d, J=5.2), 2.52 (2H, t, J=7.2),1.88 (2H, brt), 1.52 (2H, m), 1.31 (2H, m), 2.40 (3H, s).

PREPARATIVE EXAMPLE 20N-Methyl-4-[4-(2-phenylethyl)homopiperazinyl]sulfonylaniline ##STR58##

A-suspension of 1-(2-phenylethyl)homopiperazine dihydrochloride (7.0 g,25 mmol) in dichloromethane (100 ml) was cooled with ice, followed bythe gradual addition of a solution of triethylamine (15.0 ml, 108 mmol)in dichloromethane (50 ml) thereto. The solid4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (6.20 g, 25.0 mmol)prepared in Preparative Example 12 was added as such to the obtainedsolution at 0° C., followed by the addition of dichloromethane (50 ml).The ice bath was taken out to raise the temperature of the resultingmixture to room temperature. The mixture was stirred for one hour and 40minutes.

A saturated aqueous solution (100 ml) of sodium hydrogencarbonate wasadded to the obtained suspension to conduct phase separation. Theaqueous layer was further extracted with dichloromethane. The organiclayers were combined, washed with a saturated aqueous solution of commonsalt, dried over magnesium sulfate, and concentrated in a vacuum. Theobtained oil (10.4 g) was purified by column chromatography[benzene/acetone (3:1)→(1:1)] to giveN-acetyl-N-methyl-4-[4-(2-phenylethyl)homopiperazinyl]sulfonylaniline asan oil (9.9 g, 94%).

This oil (9.9 g) was dissolved in dioxane (40 ml), followed by theaddition of 4N hydrochloric acid (100 ml). The obtained mixture washeated under reflux for one hour and 15 minutes.

The obtained solution was cooled by allowing to stand and concentratedin a vacuum. The obtained residue was cooled with ice, followed by thesuccessive addition of water (50 ml) and concentrated aqueous ammonia(50 ml) in this order. The obtained mixture was extracted withdichloromethane. The organic layer was washed with a saturated aqueoussolution of common salt, dried over magnesium sulfate and dried in avacuum. The obtained oil (9.0 g) was purified by column chromatography[benzene/acetone (10:1)→(5:1)] to give the title compound as an oil(8.26 g, 93%).

¹ H-NMR (400 MHz, CDCl₃) δ: 7.58 (2H, d, J=8.9), 7.26 (2H, m), 7.17 (3H,m), 6.58 (2H, d, J=8.9), 4.23 (1H, brq, J=5.1), 3.34 (4H, m), 2.88 (3H,d, J=5.1), 2.75 (4H, m), 2.73 (4H, s), 1.83 (2H, quint, J=6.0).

PREPARATIVE EXAMPLES 21 TO 58

Amine derivatives of Preparative Examples 21 to listed in Table 3 wereeach prepared in a similar manner to that described in one ofPreparative Examples 12 to 20.

                                      TABLE 3                                     __________________________________________________________________________     ##STR59##                                                                     ##STR60##                                                                         ##STR61##                                                                             ##STR62##                                                                                              ##STR63##                                                                            ##STR64##                        __________________________________________________________________________    21  H                                                                                      ##STR65##               102˜107                                                                         ##STR66##                        22  H                                                                                      ##STR67##               139˜140                                                                         ##STR68##                        23  H                                                                                      ##STR69##               119˜122                                                                         ##STR70##                        24  CH.sub.3                                                                              NHCH.sub.3               143˜148                                                                        (90 MHz, DMSO-d.sub.6):                                                       7.56 (2H, br, D.sub.2 O                                                       exchange), 7.50                                                               (2H, d, J=8.4), 6.75 (2H, d,                                                  J=8.4),                                                                       2.72 (3H, s), 2.32 (3H, s)        25  CH.sub.3                                                                               ##STR71##                                                                                              ##STR72##                                                                            ##STR73##                        26  CH.sub.3                                                                               ##STR74##               oil                                                                                   ##STR75##                        27  CH.sub.3                                                                               ##STR76##               143˜147                                                                         ##STR77##                        28  CH.sub.3                                                                              NH.sub.2                 166˜167                                                                        400 MHz, DMSO-d.sub.6):                                                       7.51 (2H, d, J=8.8), 6.91                                                     (2H, s), 6.57                                                                 (2H, d, J=8.8), 6.37 (1H,                                                     brq, J=5.0),                                                                  2.71 (3H, d, J = 5.0)             29  CH.sub.3                                                                               ##STR78##               130˜131                                                                         ##STR79##                        30  CH.sub.3                                                                               ##STR80##               126˜127                                                                         ##STR81##                        31  CH.sub.3                                                                               ##STR82##               130˜135                                                                         ##STR83##                        32  CH.sub.3                                                                               ##STR84##               117˜119                                                                         ##STR85##                        33  CH.sub.3                                                                               ##STR86##               161˜162                                                                         ##STR87##                        34  CH.sub.3                                                                               ##STR88##               110˜113                                                                         ##STR89##                        35  CH.sub.3                                                                               ##STR90##               196˜201                                                                         ##STR91##                        36  CH.sub.3                                                                               ##STR92##                99˜100                                                                         ##STR93##                        37  CH.sub.3                                                                               ##STR94##               oil                                                                                   ##STR95##                        38  CH.sub.3                                                                               ##STR96##               170˜172                                                                         ##STR97##                        39  CH.sub.3                                                                               ##STR98##               139˜143                                                                         ##STR99##                        40  CH.sub.3                                                                               ##STR100##                                                                                             ##STR101##                                                                           ##STR102##                       41  CH.sub.3                                                                               ##STR103##              169˜176                                                                         ##STR104##                       42  CH.sub.3                                                                               ##STR105##              109˜110                                                                         ##STR106##                       43  CH.sub.3                                                                               ##STR107##              oil                                                                                   ##STR108##                       44  CH.sub.3                                                                               ##STR109##              102˜103                                                                         ##STR110##                       45  CH.sub.3                                                                               ##STR111##              amorphous                                                                             ##STR112##                       46  CH.sub.3                                                                               ##STR113##              145˜146                                                                         ##STR114##                       47  CH.sub.3                                                                               ##STR115##              123˜124                                                                         ##STR116##                       48                                                                                 ##STR117##                                                                           NH.sub.2                 138-139                                                                               ##STR118##                       49  CH.sub.3                                                                               ##STR119##              150˜152                                                                         ##STR120##                       50  CH.sub.3                                                                               ##STR121##              oil                                                                                   ##STR122##                       51  CH.sub.3                                                                               ##STR123##              146˜147                                                                         ##STR124##                       52  CH.sub.3                                                                               ##STR125##              155˜156                                                                         ##STR126##                       53  CH.sub.3                                                                               ##STR127##              203-204                                                                               ##STR128##                       54  CH.sub.3                                                                               ##STR129##              140˜141                                                                         ##STR130##                       55  CH.sub.3                                                                               ##STR131##              122˜123                                                                         ##STR132##                       56  CH.sub.3                                                                               ##STR133##              120˜128                                                                         ##STR134##                       57  CH.sub.3                                                                               ##STR135##              136˜140                                                                         ##STR136##                       58  CH.sub.3                                                                               ##STR137##              125˜127                                                                         ##STR138##                       __________________________________________________________________________     In Preparative Examples 21 to 23, known 4(N-acetylamino)benzenesulfonyl       chloride was used instead of the 4(N-acetyl-N-methylamino)benzenesulfonyl     chloride prepared in Preparative Example 12.                             

EXAMPLE 1 Synthesis of Compound 99

N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(3,4-diacetoxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR139##

A solution of 3,4-diacetoxycinnamoyl chloride (5.61 g, 19.9 mmol) indichloromethane (50 ml) was dropped into a solution of theN-(2-indanyl)-4-(methylamino)benzenesulfonamide (5.00 g, 16.6 mmol)prepared in Preparative Example 14 in pyridine (50 ml) at 0° C. Theobtained mixture was stirred at room temperature for 2 hours, followedby the addition of water. The obtained mixture was extracted with ethylacetate. The organic layer was washed with 1N aqueous hydrochloric acidand a saturated aqueous solution of common salt, dried over magnesiumsulfate, and concentrated to give a solid residue. This residue wasrecrystallized from ethyl acetate/ether/isopropyl ether to give thetitle compound as a white crystal (8.90 g, 100%).

m.p. (°C.): 152˜153 (iso-Pr₂ O)

¹ H-NMR (400 MHz, DMSO-d₆) δ: 8.11 (1H, d, J=7.2), 7.91 (2H, d, J=8.8),7.58 (2H, d, J=8.8), 7.58˜7,42 (3H, m), 7.20 (1H, d, J=8.4), 7.11 (4H,s), 6.61 (1H, brd, J=15.4), 3.94 (1H, m), 3.38 (3H, s), 2.98 (2H, dd,J=16.8), 2.75 (2H, dd, J=16.8), 2.26 (3H, s), 2.18 (3H, s)

Mass m/e (FAB): 549 (MH⁺), 507, 307, 205, 154 (base)

    ______________________________________                                        elemental analysis as C.sub.29 H.sub.28 N.sub.2 O.sub.7 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             63.49       5.14   5.11                                          found (%)    63.57       5.19   4.87                                          ______________________________________                                    

EXAMPLE 2

N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR140##

TheN-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide(8.90 g, 16.6 mmol) prepared in Example 1 was suspended in a mixturecomprising methanol (80 ml) and tetrahydrofuran (80 ml), followed by theaddition of concentrated hydrochloric acid (30 ml). The obtained mixturewas stirred at 60° C. for 20 minutes, followed by the addition of water.The obtained mixture was extracted with ethyl acetate. The organic layerwas washed with water and a saturated aqueous solution of common salt,dried over magnesium sulfate, and concentrated to give a solid residue.The residue was recrystallized from ether to give the title compound asa white crystal (7.17 g, yield: 93%).

m.p. (°C.): 201˜203 (Et₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.20, 8.00 (each 1H, br, D₂ O exchange),7.92 (2H, d, J=8.3Hz), 7.55 (2H, d, J=8.4Hz), 7.40 (1H, d, J=15.4Hz),7.11 (4H, s), 6.87˜6.35 (3H, m), 6.22 (1H, d, J=15.4Hz), 3.88 (1H, m, D₂O sharpen), 3.35 (3H, s), 3.15˜2.55 (4H, m)

Mass m/e (FD): 464 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.24 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             64.64       5.21   6.03                                          found (%)    64.80       5.37   5.92                                          ______________________________________                                    

EXAMPLE 3

N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(3,4-diglycyloxyphenyl)-2-propenoyl]amino}benzenesulfonamidedihydrochloride ##STR141##

Dicyclohexylcarbodiimide (DCC, 0.27 g) was added to a suspension of theN-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide(0.30 g, 0.65 mmol) and N-(tert-butoxycarbonyl)glycine (0.23 g, 1.29mmol) in ethyl acetate (7 ml). The obtained mixture was stirred at roomtemperature overnight and filtered. The filtrate was concentrated togive an N-BOC derivative of the title compound as a white crystal (0.47g, yield: 92 %). This crystal (0.42 g, 0.537 mmol) was dissolved inethyl acetate (2.0 ml), followed by the addition of a 1.5N solution (2.0ml) of hydrochloric acid in ethyl acetate. The obtained mixture wasstirred at room temperature for one hour.

The precipitated crystal was recovered by filtration to give the titlecompound as a white crystal (0.32 g, yield: 91%).

m.p. (°C.): 120˜127 (AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.73 (6H, br, D₂ O exchange), 8.17 (1H, d,J=7.0H₂, D₂ O exchange), 7.92 (2H, d, J=8.8Hz), 6.91˜7.75 (6H, m), 7.11(4H, s), 6.60 (1H, d, J=15.4Hz), 4.19 (4H, m), 3.98 (3H, m), 3.39 (3H,s), 3.20˜2.56 (4H, m)

Mass m/e (FAB): 579 (MH⁺), 522, 465, 410, 282, 225, 185 (base)

    ______________________________________                                        elemental analysis as C.sub.29 H.sub.30 N.sub.4 O.sub.7 S.2HCl.1/3H.sub.2                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             52.98       4.70   8.52                                          found (%)    52.78       5.10   8.15                                          ______________________________________                                    

EXAMPLE 4

N-(1-Benzyl-4-piperidyl)-4-{N-methyl-N-I(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide##STR142##

The 3-(4-methylsulfonyl) cinnamic acid (1.56 g, 6.67 mmol) prepared inPreparative Example 5 was suspended in dichloromethane (20 ml), followedby the addition of oxalyl chloride (2.01 ml, 23.3 mmol) anddimethylformamide (two drops). The obtained mixture was stirred at roomtemperature for one hour and concentrated to give3-(4-methylsulfonyl)cinnamoyl chloride as a white crystal. This chloridewas dissolved in dichloromethane (25 ml) to obtain a solution. Thissolution was dropped into a solution of theN-(1-benzyl-4-piperidyl)-4-(N-methylamino)benzenesulfonamidedihydrochloride (2.62 g, 6.06 mmol) prepared in Preparative Example 16in pyridine (25 ml) at 0° C. The obtained mixture was stirred at roomtemperature for 2 hours, followed by the addition of water. The obtainedmixture was extracted with ethyl acetate. The organic layer was washedwith water and a saturated aqueous solution of common salt, dried overmagnesium sulfate, and concentrated to give a solid residue. Thisresidue was purified by flash column chromatography(chloroform/methanol/aqueous ammonia=98:2:0.2) and recrystallized fromethyl acetate/ether to give the title compound as a white crystal (2.60g, yield: 76%).

m.p. (°C.): 189˜190 (AcOEt-Et₂ O)

¹ H-NMR (400 MHz, CDCl₃) δ: 7.95 (2H, d, J=8.6Hz), 7.88 (2H, d,J=8.4Hz), 7.74 (1H, d, J=15.4Hz), 7.50 (2H, d, J=8.4Hz), 7.36 (2H, d,J=8.6Hz), 7.27 (5H, m), 6.45 (1H, d, J=15.4Hz), 4.27 (1H, d, J=7.7Hz),3.46 (2H, s), 3.46 (3H, s), 3.27 (1H, m), 3.02 (3H, s), 2.75 (1H, brd,J=12.1Hz), 2.05 (2H, t like, J=8Hz), 1.80 (2H, m), 1.52 (2H, m)

Mass m/e (FAB): 568 (MH⁺), 490, 360, 209, 189, 172 (base)

    ______________________________________                                        elemental analysis as C.sub.29 H.sub.33 N.sub.3 O.sub.5 S.sub.2                          C         H      N                                                 ______________________________________                                        calculated (%)                                                                             61.36       5.85   7.40                                          found (%)    61.08       5.98   7.42                                          ______________________________________                                    

EXAMPLE 5

N-[1-(2-Phenylethyl)-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide##STR143##

A solution of 3-(4-methylsulfonyl)cinnamoyl chloride [3.10 mmol,prepared from 3-(4-methylsulfonyl)cinnamic acid (0.70 g) in a similarmanner to that of Example 4] in dichloromethane (10 ml) was dropped intoa solution of theN-11-(2-phenylethyl)-4-piperidyl]-4-(N-methylamino)benzenesulfonamidedihydrochloride (1.26 g, 2.82 mmol) prepared in Preparative Example 18in pyridine (20 ml) at 0° C. The obtained mixture was stirred at roomtemperature for 2 hours, followed by the addition of water. The obtainedmixture was extracted with ethyl acetate. The organic layer was washedwith water and a saturated aqueous solution of common salt, dried overmagnesium sulfate, and concentrated to give a solid residue. The residuewas recrystallized from ethyl acetate/ether to give the title compoundas a white crystal (1.04 g, yield: 63%).

m.p. (°C.): 173˜176 (AcOEt-Et₂ O)

¹ H-NMR (400 MHz, CDCl₃) δ: 7.96 (2H, d, J=8.6Hz), 7.87 (2H, d,J=8.4Hz), 7.74 (1H, d, J=15.6Hz), 7.50 (2H, d, J=8.4Hz), 7.37 (2H, d,J=8.6Hz), 7.28 (2H,m), 7.17 (3H, m), 6.46 (1H, d, J=15.6Hz), 4.68 (1H,d, J=6.0), 3.46 (3H, s), 3.28 (1H, m), 3.01 (3H, s), 2.86 (2H, brd,J=12.3Hz), 2.75 (2H, m), 2.56 (2H, m), 2.11 (2H, brt, J=8Hz), 1.87 (2H,m), 1.55 (2H, m)

Mass m/e (FAB): 582 (MH⁺), 490, 307, 154 (base)

    ______________________________________                                        elemental analysis as C.sub.30 H.sub.35 N.sub.3 O.sub.5 S.sub.2                          C         H      N                                                 ______________________________________                                        calculated (%)                                                                             6.194       6.06   7.22                                          found (%)    61.67       6.09   7.05                                          ______________________________________                                    

EXAMPLES 6 TO 99

The compounds of Examples 6 to 99 which will be described below wereeach prepared in a similar manner to that of Example 4 or 5.

EXAMPLE 6

N-Methyl-N-[2-(6-methyl-2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamidehydrochloride ##STR144##

m.p. (°C.): 164˜167 (EtOH-AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.38 (1H, t, J=7.9Hz), 8.00˜7.44 (11H, m),6.76 (1H, d, J=15.4Hz), 3.60˜3.20 (4H, m), 3.40 (3H, s), 3.21 (3H, s),2.83 (3H, s), 2.78 (3H, s)

Mass m/e (FAB): 528 (MH⁺ base), 314, 209, 170, 149, 107

    ______________________________________                                        elemental analysis as C.sub.26 H.sub.29 N.sub.3 O.sub.5 S.sub.2.HCl                      C         H      N                                                 ______________________________________                                        calculated (%)                                                                             55.36       5.36   7.45                                          found (%)    55.26       5.15   7.29                                          ______________________________________                                    

EXAMPLE 7

(E)-N-Methyl-N-{4-[4-(2-phenylethyl]homopiperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide##STR145##

m.p. (°C.): 203˜207 (EtOH-AcOEt-MeOH)

¹ H-NMR (400 MHz, CDCl₃ -DMSOd₆ (10:1)) δ: 7.92 (2H, d, J=8.4 Hz), 7.85(2H, d, J=8.4 Hz), 7.76 (1H, d, J=15.5 Hz), 7.56 (2H, d, J=8.4 Hz), 7.44(2H, d, J=8.4 Hz), 7.35˜7.23 (5H, m), 6.51 (1H, d, J=15.5 Hz), 3.81 (2H,m), 3.49 (3H, s), 3.27 (6H, m), 3.06 (3H, s), 2.48 (6H, m)

Mass m/e (FAB): 582 (MH⁺), 490, 372, 111 (base)

    ______________________________________                                        elemental analysis as C.sub.30 H.sub.35 N.sub.3 O.sub.5 S.sub.2.HCl                      C         H      N                                                 ______________________________________                                        calculated (%)                                                                             58.28       5.87   6.80                                          found (%)    58.20       5.67   6.71                                          ______________________________________                                    

EXAMPLE 8(±)-N-[1-(2-Pyridylmethyl)-3-hexamethyleneimino]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamidedihydrochloride ##STR146##

m.p. (°C.): 145˜148 (Et₂ O-AcOEt)

1H-NMR (400 MHz, DMSO-d₆ δ (free form): 7.87 (2H, d, J=8.4 Hz), 7.85(2H, d, J=8.8 Hz), 7.73 (1H, d, J=15.6 Hz), 7.51 (2H, d, J=8.2 Hz),7.37˜7.21 (6H, m), 6.44 (1H, d, J=15.6 Hz), 3.87 (1H, d, J=13.2 Hz),3.51 (1H, dd, J=14.2, 3.9 Hz), 3.44 (3H, s), 3.35 (1H, m), 3.28 (1H, m),3.07 (1H, dd, J=14.2, 7.6 Hz), 3.02 (3H, s), 2.92 (1H, m), 2.00˜1.60(4H, m), 1.47 (2H, m)

Mass m/e (FAB): 582 (MH⁺), 475, 374, 203, 106 (base)

High MASS: as C₂₉ H₃₄ N₄ O₅ S₂ calculated (%) 582.1970 (M⁺) found (%)582.1964

EXAMPLE 9(±)-N-[1-Benzyl-3-hexamethyleneimino]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide##STR147##

m.p. (°C.): 88˜92 (amorphous, iso-Pr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.00˜7.32 (10H, m), 7.23 (5H, m), 6.61 (1H,d, J=15.3 Hz), 3.49 (2H, s), 3.18 (3H, s), 1.80˜1.20 (6H, m)

Mass m/e (FAB): 582 (MH⁺, base), 232, 203, 188

High MASS: as C₃₀ H₃₅ N₃ O₅ S₂ calculated (%) 582.2097 (MH⁺) found (%)582.2102

EXAMPLE 10N-[1-(2-Methylpropyl)-4-piperidyl)-4-{N-methyl-N-(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide##STR148##

m.p. (°C.): 147˜148 (AcOEt-Et₂ O )

¹ H-NMR (400 MHz, CDCl₃) δ: 7.96 (2H, d, J=8.6 Hz), 7.87 (2H, d, J=8.4Hz), 7.74 (1H, d, J=15.6 Hz), 7.50 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.6Hz), 6.45 (1H, d, J=15.6 Hz), 4.82 (1H, br), 3.46 (3H, s), 3.27 (1H, m),3.02 (3H, s), 2.78 (1H, brd, J=12.3 Hz), 2.09 (2H, d, J=6.0 Hz), 2.04(2H, brt, J=8 Hz), 1.90˜1.64 (3H, m), 1.60 (2H, m)

Mass m/e (FAB): 582 (MH⁺), 490, 324, 209, 140 (base), 112

    ______________________________________                                        elemental analysis as C.sub.26 H.sub.35 N.sub.3 O.sub.5 S.sub.2.0.4H.sub.2     O                                                                                       C         H      N                                                 ______________________________________                                        calculated (%)                                                                             57.73       6.67   7.77                                          found (%)    57.50       6.39   7.54                                          ______________________________________                                    

EXAMPLE 11 N-(1-Methyl-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide##STR149##

m.p. (°C.): 122˜125 (AcOEt)

¹ H-NMR (90 MHz, CDCl₃) δ: 7.96 (2H, d, J=8.6 Hz), 7.88 (2H, d, J=8.6Hz), 7.74 (1H, d, J=15.8 Hz), 7.49 (2H, d, J=8.6 Hz), 7.37 (2H, d, J=8.6Hz), 6.44 (1H, d, J=15.8 Hz), 3.47 (3H, s), 3.3 (1H, m), 3.03 (3H, s),2.7 (2H, m), 2.24 (3H, s), 2.1˜1.4 (6H, m)

Mass m/e (FAB): 492 (MH⁺, base), 315, 282, 209, 170

    ______________________________________                                        elemental analysis as C.sub.23 H.sub.29 N.sub.3 O.sub.5 S.sub.2                          C         H      N                                                 ______________________________________                                        calculated (%)                                                                             56.19       5.95   8.55                                          found (%)    56.13       6.11   8.17                                          ______________________________________                                    

EXAMPLE 12N-(3-Quinuclidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide##STR150##

m.p. (°C.): 221˜222 (EtOH-MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.46 (1H, d, J=6.5 Hz, D₂ O exchange),8.00˜7.40 (9H, m), 6.73 (1H, d, J=15.4 Hz), 3.39 (3H, s), 3.21 (3H, s),3.80˜2.80 (8H, m), 2.10˜1.50 (4H, m)

Mass m/e (FAB): 504 (MH⁺), 277, 185 (base), 125

    ______________________________________                                        elemental analysis as C.sub.24 H.sub.29 N.sub.3 O.sub.5 S.sub.2.2.5H.sub.2     O                                                                                       C         H      N                                                 ______________________________________                                        calculated (%)                                                                             52.53       6.24   7.66                                          found (%)    52.18       5.57   7.34                                          ______________________________________                                    

EXAMPLE 13N-[3-(N,N-Dimethylamino)propyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2propenoyl]amino}benzenesulfonamidehydrochloride ##STR151##

m.p. (°C.): 201˜204 (MeOH)

¹ H NMR (400 MHz, DMSO-d₆) δ: 7.94 (1H, t, J=6.0 Hz), 7.88 (2H, d, J=7.7Hz), 7.86 (2H, d, J=8.4 Hz), 7.78 (2H, d, J=7.7 Hz), 7.62 (1H, d, J=15.6Hz), 7.56 (2H, d, J=8.4 Hz), 6.76 (1H, brd, J=15.6 Hz), 3.38 (3H, s),3.36 (3H, s), 3.01 (2H, dd, J=7.0, 6.0 Hz), 2.86 (2H, q, J=6.0 Hz), 1.82(2H, quint, J=7.7 Hz)

Mass m/e (FAB): 480 (MH⁺, base), 259, 209, 167, 149

    ______________________________________                                        elemental analysis as C.sub.22 H.sub.29 N.sub.3 O.sub.5 S.sub.2 HCl                      C         H      N                                                 ______________________________________                                        calculated (%)                                                                             51.20       5.86   8.14                                          found (%)    50.86       5.86   7.99                                          ______________________________________                                    

EXAMPLE 14N-Cycloheptyl-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide##STR152##

m.p. (°C.): 146˜148 (MeOH)

¹ H-NMR (90 MHz, CDCl₃) δ: 7.94 (1H, d, J=8.8 Hz), 7.87 (2H, d, J=8.4Hz), 7.74 (1H, d, J=15.4 Hz), 7.49 (2H, d, J=8.4 Hz), 7.36 (2H, d, J=8.8Hz), 6.43 (1H, d, J=15.4 Hz), 4.59 (1H, d, J=8.4 Hz), 3.46 (3H, s), 3.46(1H, m), 3.03 (3H, s), 2.00˜1.30 (12H, m)

Mass m/e (FD): 490 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.24 H.sub.30 N.sub.2 O.sub.5 S.sub.2                          C         H      N                                                 ______________________________________                                        calculated (%)                                                                             58.75       6.16   5.71                                          found (%)    58.51       6.15   5.60                                          ______________________________________                                    

EXAMPLE 15N-[2-(6-methyl-2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamidehydrochloride ##STR153##

m.p. (°C.): 169˜175 (AcOEt)

¹ H-NMR (400 MHz, CMSO-d₆) δ: 7.94 (2H, d, J=8.6 Hz), 7.83 (2H, d, J=8.2Hz), 7.72 (1H, d, J=15.6 Hz), 7.48 (3H, m), 7.34 (2H, d, J=8.6 Hz), 7.00(1H, d, J=7.5 Hz), 6.90 (1H, d, J=7.7 Hz), 6.60 (1H, brt), 6.43 (1H, d,J=15.6 Hz), 3.44 (3H, s), 3.42 (2H, m), 2.94 (2H, t, J=6.0 Hz), 2.48(3H, s), 3.02 (3H, s)

Mass m/e (FAB): 514 (MH⁺, base), 498, 304

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.27 N.sub.3 O.sub.5 S.sub.2.0.2H.sub.2     O                                                                                       C         H      N                                                 ______________________________________                                        calculated (%)                                                                             54.23       5.17   7.59                                          found (%)    54.07       5.03   7.42                                          ______________________________________                                    

EXAMPLE 16N-[3-(4-Pyridyl)propyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR154##

m.p. (°C.): amorphous (CH₂ Cl₂)

¹ H-NMR (400 MHz, CDCl₃) δ: 8.48 (2H, d, J=6.0 Hz), 7.93 (2H, d, J=8.6Hz), 7.87 (2H, d, J=8.4 Hz), 7.75 (1H, d, J=15.6 Hz), 7.51 (2H, d, J=8.4Hz), 7.38 (2H, d, J=8.6 Hz), 7.09 (2H, d, J=6.0 Hz), 6.47 (1H, d, J=15.6Hz), 5.05 (1H, t, J=7 Hz), 3.46 (3H, s), 3.05 (2H, m), 2.69 (2H, t,J=7.7 Hz), 1.89 (2H, quint, J=7.7 Hz)

Mass m/e (FAB):

High MASS: as C₂₅ H₂₇ N₃ O₅ S₂ calculated (%) 514.1470 (MH⁺) found (%)514.1471

EXAMPLE 17N-Methyl-N-[2-(2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamidehydrochloride ##STR155##

m.p. (°C.): 153˜159 (AcOEt)

¹ H-NMR (400 MHz, DMSO-d₆) δ: 8.79 (1H, d, J=8 Hz), 8.46 (1H, t, J=8Hz), 7.97 (1H, d, J=8 Hz), 7.85 (3H, m), 7.76 (4H, m), 7.60 (1H, d,J=15.6 Hz), 7.55 (2H, dd, J=8.2 Hz), 6.74 (1H, d, J=15.6 Hz), 3.46 (2H,d, J=6 Hz), 3.38 (3H, s), 3.30 (2H, t, J=6 Hz), 3.18 (3H, s), 2.79 (3H,s)

Mass m/e (FAB): 514 (MH⁺, base), 378, 314, 209, 170

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.27 N.sub.3 O.sub.5 S.sub.2.HCl.0.1H.s    ub.2 O                                                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             54.40       5.33   7.61                                          found (%)    51.17       5.01   7.38                                          ______________________________________                                    

EXAMPLE 18N-[2-(2-Pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide##STR156##

m.p. (°C.): 143˜144 (Et₂ O -EtOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.43 (1H, d like, J=6.0 Hz), 7.96˜7.40(10H, m), 7.17 (1H, d like, J=7.5 Hz), 6.71 (1H, d, J=15.4 Hz), 3.39(3H, s), 3.19 (3H, s), 3.30˜3.00 (2H, m), 2.85 (1H, t like, J=6.6 Hz)

Mass m/e (FD): 499 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.24 H.sub.25 N.sub.3 O.sub.5 S.sub.2.0.5H.sub.2     O                                                                                       C         H      N                                                 ______________________________________                                        calculated (%)                                                                             56.67       5.15   8.26                                          found (%)    56.67       4.93   8.17                                          ______________________________________                                    

EXAMPLE 19N-(2-Pyridylmethyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamidehydrochloride ##STR157##

m.p. (°C.): 125˜128 (CH₂ Cl₂ -EtOH-MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.78 (1H, d D₂ O exchange), 8.68 (1H, d,J=5.0 Hz), 8.34 (1H, t, J=8.0 Hz), 8.00˜7.45 (11H, m), 6.74 (1H, d,J=15.8 Hz), 4.45 (2H, s), 3.39 (3H, s), 3.20 (3H, s)

Mass m/e (FAB): 486 (MH⁺), 314, 278, 209, 170, 131, 107 (base)

    ______________________________________                                        elemental analysis as C.sub.23 H.sub.23 N.sub.3 O.sub.5 S.sub.2.HCl                      C         H      N                                                 ______________________________________                                        calculated (%)                                                                             52.92       4.63   8.05                                          found (%)    52.85       4.57   7.70                                          ______________________________________                                    

EXAMPLE 20(E)-N-Methyl-N-[4-(4-cyclohexylmethyl-1-homopiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamidehydrochloride ##STR158##

m.p. (°C.): 212˜216 (AcOEt-MeOH-EtOH)

¹ H-NMR (400 MHz, CDCl₃) δ: 11.95 (1H, brs), 7.91 (2H, d, J=8.2 Hz),7.82 (2H, d, J=8.2 Hz), 7.75 (1H, d, J=15.5 Hz), 7.54 (2H, d, J=8.2 Hz),7.41 (2H, d, J=8.2 Hz), 6.48 (1H, d, J=15.5 Hz), 3.95˜3.55 (5H, m), 3.48(3H, s), 3.30˜2.85 (6H, m), 3.05 (3H, s), 2.20 (1H, m), 2.05˜1.65 (6H,m), 1.35˜1.00 (5H, m)

Mass m/e (FAB): 574 (MH⁺), 394, 364, 195 (base)

    ______________________________________                                        elemental analysis as C.sub.29 H.sub.39 N.sub.3 O.sub.5 S.sub.2.HCl.0.3H.s    ub.2 O                                                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             56.58       6.65   6.83                                          found (%)    56.60       6.48   6.69                                          ______________________________________                                    

EXAMPLE 21(E)-N-Methyl-N-[4-(4-benzyl-1-homopiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamidehydrochloride ##STR159##

m.p. (°C.): 196˜199 (AcOEt)

¹ H-NMR (400 MHz, CDCl₃ -DMSO-d₆) δ: 11.95 (1H, brs), 7.91 (2H, d, J=8.4Hz), 7.82 (2H, d, J=8.9 Hz), 7.73 (1H, d, J=15.6 Hz), 7.70 (2H, m), 7.58(2H, d, J=8.9 Hz), 7.45 (2H, d, J=8.4 Hz), 7.45 (3H, m), 6.54 (1H, d,J=15.6 Hz), 4.38 (1H, m), 4.28 (1H, m), 3.91 (1H, m), 3.73 (1H, m), 3.57(2H, m), 3.48 (3H, s), 3.33˜3.11 (3H, m), 3.08 (3H, s), 2.75 (1H, m),2.17 (1H, m)

Mass m/e (FAB): 568 (MH⁺), 359, 315, 209, 189 (base)

    ______________________________________                                        elemental analysis as C.sub.29 H.sub.33 N.sub.3 O.sub.5 S.sub.2.HCl                      C         H      N                                                 ______________________________________                                        calculated (%)                                                                             57.65       5.67   6.96                                          found (%)    57.36       5.77   6.61                                          ______________________________________                                    

EXAMPLE 22(E)-N-Methyl-N-{4-{4-(2-phenylethyl)piperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide##STR160##

m.p. (°C.): 193˜194 (AcOEt)

¹ H-NMR (400 MHz, CDCl₃) δ: 7.90 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=8.6Hz), 7.77 (1H, d, J=15.6 Hz), 7.54 (2H, d, J=8.3 Hz), 7.42 (2H, d, J=8.6Hz), 7.28 (2H, m), 7.21 (1H, d, J=6.2 Hz), 7.17 (2H, d, J=6.8 Hz), 6.48(1H, d, J=15.6 Hz), 3.48 (1H, s), 3.14 (3H, s), 3.04 (3H, s), 2.77 (2H,m), 2.66 (4H, m)

Mass m/e (FAB): 568 (MH⁺), 476, 209, 136 (base)

    ______________________________________                                        elemental analysis as C.sub.29 H.sub.33 N.sub.3 O.sub.5 S.sub.2                          C         H      N                                                 ______________________________________                                        calculated (%)                                                                             61.35       5.86   7.40                                          found (%)    61.36       5.87   7.21                                          ______________________________________                                    

EXAMPLE 23(E)-N-Methyl-N-{4-[4-(3-pyridylmethyl)piperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide##STR161##

m.p. (°C.): 194˜196 (CH₂ Cl₂ -EtOH-isoPr₂ O)

¹ H-NMR (400 MHz, CDCl₃) δ: 8.50 (2H, s), 7.88 (2H, d, J=8.2 Hz), 7.82(2H, d, J=8.4 Hz), 7.73 (1H, d, J=15.4 Hz), 7.56 (1H, brd, J=7.7 Hz),7.51 (2H, d, J=8.2 Hz), 7.39 (2H, d, J=8.4 Hz), 7.23 (1H, dd, J=7.7, 4.8Hz), 6.45 (1H, d, J=15.4 Hz), 3.53 (2H, s), 3.46 (3H, s), 3.09 (4H,brs), 3.02 (3H, s), 2.57 (4H, t, J=4.6 Hz)

Mass m/e (FAB): 555 (MH⁺), 347, 209, 176 (base)

    ______________________________________                                        elemental analysis as C.sub.27 H.sub.30 N.sub.4 O.sub.5 S.sub.2                          C         H      N                                                 ______________________________________                                        calculated (%)                                                                             58.46       5.45   10.10                                         found (%)    58.17       5.37   9.95                                          ______________________________________                                    

EXAMPLE 24(E)-N-methyl-N-[4-(4-benzylpiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamidehydrochloride ##STR162##

m.p. (°C.): 194˜196 (CH₂ Cl₂)

¹ H-NMR (400 MHz, DMSO-d₆) δ: 7.89 (4H, s), 7.80 (2H, d, J=7.2 Hz), 7.65(1H, d, J=15.6 Hz), 7.63 (2H, d, J=7.2 Hz), 7.60 (2H, m), 7.43 (3H, m),6.76 (1H, brd, J=15.6 Hz), 4.30 (2H, brs), 3.74 (2H, brs), 3.39 (3H, s),3.3 (4H), 3.19 (3H, s), 2.95 (2H, brs)

Mass m/e (FAB): 554 (MH⁺), 346, 259, 207, 149, 115 (base)

    ______________________________________                                        elemental analysis as C.sub.28 H.sub.31 N.sub.3 O.sub.5 S.sub.2.HCl.0.5H.s    ub.2 O                                                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             56.13       5.55   7.01                                          found (%)    55.85       5.48   6.99                                          ______________________________________                                    

EXAMPLE 25N-Cycloheptyl-4-{N-methyl-N-I(E)-3-(4-cyanophenyl)-2-propenoyl]amino}benzenesulfonamide##STR163##

m.p. (°C.): 170˜171 (Et₂ O -AcOEt)

¹ H-NMR (90 MHz, CDCl₃) δ: 8.00˜7.40 (10H, m), 6.63 (1H, d, J=15.8 Hz),3.40 (3H, s), 3.20 (1H, m), 1.80˜1.00 (12H, m)

Mass m/e (FAB): 438 (MH⁺, base), 342, 262, 156, 136

    ______________________________________                                        elemental analysis as C.sub.24 H.sub.27 N.sub.3 O.sub.3 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             65.88       6.22   9.60                                          found (%)    65.83       6.17   9.41                                          ______________________________________                                    

EXAMPLE 26N-(1-Benzyl-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-cyanophenyl)-2-propenoyl]amino}benzenesulfonamidehydrochloride ##STR164##

m.p. (°C.): 180˜183 (AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.12 (1H, d, J=7.0 Hz, D₂ O exchange),8.00˜7.32 (14H, m), 6.67 (1H, d, J=15.9 Hz), 4.20 (2H, m, D₂ Oexchange), 3.40 (3H, s), 3.60˜2.60 (5H, m), 2.20˜1.60 (4H, m)

Mass m/e (FD): 514 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.29 H.sub.30 N.sub.4 O.sub.3 S.HCl.0.7H.sub.2                 C         H      N                                                 ______________________________________                                        calculated (%)                                                                             61.79       5.75   9.93                                          found (%)    61.84       5.59   9.95                                          ______________________________________                                    

EXAMPLE 27N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(4-(1-imidazoyl)phenyl]-2-propenoyl]amino}benzenesulfonamide##STR165##

m.p. (°C.): 213˜215 (AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.25 (1H, s), 8.20 (1H, d, J=7.5 Hz, D₂ Oexchange), 8.04 (2H, d, J=9.2 Hz), 7.80˜7.40 (3H, m), 7.61 (4H, s), 7.09(4H, s), 6.60 (1H, d, J=15.4 Hz), 3.92 (1H, m), 3.40 (3H, s), 3.20˜2.57(4H, m)

Mass m/e (FD): 498 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.28 H.sub.26 N.sub.4 O.sub.3 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             67.45       5.26   11.24                                         found (%)    67.19       5.20   11.17                                         ______________________________________                                    

EXAMPLE 28N-[1-(1,2,3,4-Tetrahydro)naphthyl]-4-{N-methyl-N-[(E)-3-(4-(1-imidazolyl)phenyl)-2-propenoyl]amino}benzenesulfonamide##STR166##

m.p. (°C.): 221˜222 (AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.28 (1H, s), 8.16 (1H, d, J=7.9 Hz), 7.96(2H, d, J=8.3 Hz), 7.79˜7.43 (4H, m), 7.61 (4H, s), 7.08 (4H, s), 7.08(1H, s), 6.55 (1H, d, J=15.8 Hz), 4.43 (1H, m), 3.39 (3H, s), 2.65 (2H,m), 1.65 (4H, m)

Mass m/e (FD): 512 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.29 H.sub.28 N.sub.4 O.sub.3 S.0.1H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             67.71       5.52   10.89                                         found (%)    67.95       5.42   10.81                                         ______________________________________                                    

EXAMPLE 29N-Cycloheptyl-4-{N-methyl-N-I(E)-3-(4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide##STR167##

m.p. (°C.): 173˜174 (AcOEt-Et₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.29 (1H, brs), 7.87 (2H, d, J=8.4 Hz),7.83˜7.40 (11H, m), 7.11 (1H, brs), 6.52 (1H, d, J=15.4 Hz), 3.37 (3H,s), 3.16 (1H, m), 1.88˜1.05 (12H, m)

Mass m/e (FAB): 479 (MH⁺, base), 383, 303, 197, 170, 144

    ______________________________________                                        elemental analysis as C.sub.26 H.sub.30 N.sub.4 O.sub.3 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             65.25       6.32   11.71                                         found (%)    65.13       6.45   11.54                                         ______________________________________                                    

EXAMPLE 30N-Cyclooctyl-4-{N-methyl-N-[(E)-3-(4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide##STR168##

m.p. (°C.): 173˜174 (AcOEt-Et₂ O ).

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.29 (1H, brs), 7.87 (2H, d, J=8.4 Hz),7.83˜7.40 (11H, m), 7.11 (1H, brs), 6.52 (1H, d, J=15.4 Hz), 3.37 (3H,s), 3.16 (1H, m), 1.88˜1.05 (12H, m)

Mass m/e (FAB): 479 (MH⁺, base), 383, 303, 197i 170, 144

    ______________________________________                                        elemental analysis as C.sub.26 H.sub.30 N.sub.4 O.sub.3 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             65.25       6.32   11.71                                         found (%)    65.13       6.45   11.54                                         ______________________________________                                    

EXAMPLE 31(±)-N-(exo-2-Norbornyl)-4-{N-methyl-N-[(E)-3-(4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide ##STR169##

m.p. (°C.): 187˜188 (AcOEt-E_(t) 2O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.28 (1H, s), 7.86 (2H, J=8.8 Hz), 7.74(1H, s), 7.69˜7.40 (4H, m), 7.61 (4H, s), 7.10 (1H, s), 6.53 (1H, d,J=15.8 Hz), 3.37 (1H, s), 3.00 (1H, m), 2.20˜1.90 (2H, m), 1.64˜0.80(8H, m)

Mass m/e (FD): 477 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.26 H.sub.28 N.sub.4 O.sub.3 S.0.7H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             63.83       6.06   11.45                                         found (%)    63.83       5.77   11.46                                         ______________________________________                                    

EXAMPLE 32(±)-N-(endo-2-Norbornyl)-4-{N-methyl-N-[(E)-3-(4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamidehydrochloride ##STR170##

m.p. (°C.): 191˜195 (AcOEt-EtOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.71 (1H, s), 8.27 (1H, s), 8.00˜7.40 (11H,m), 6.61 (1H, d, J=15.8 Hz), 3.38 (1H, s), 2.03 (2H, m), 2.00˜0.70 (8H,m)

Mass m/e (FAB): 477 (MH⁺, base), 303, 197, 144, 115

    ______________________________________                                        elemental analysis as C.sub.26 H.sub.28 N.sub.4 O.sub.3 S.HCl.0.1H.sub.2                 C         H      N                                                 ______________________________________                                        calculated (%)                                                                             63.83       6.06   11.45                                         found (%)    63.83       5.77   11.46                                         ______________________________________                                    

EXAMPLE 33N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide##STR171##

m.p. (°C.): 241˜242 (AcOEt-iso-Pr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.14 (2H, d, J=8.8 Hz), 8.1 (1H), 7.93 (2H,d, J=8.8 Hz), 7.76 (2H, d, J=8.8 Hz), 7.66 (1H, d, J=15.6 Hz), 7.58 (2H,d, J=8.8 Hz), 7.10 (4H, s), 6.76 (1H, d, J=15.6 Hz), 3.99 (1H, m), 3.41(3H, s), 2.99 (2H, dd, J=15.8, 7.5 Hz), 2.70 (2H, dd, J=15.8, 7.5 Hz)

Mass-m/e (FD): 477 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.23 N.sub.3 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             62.88       4.86   8.80                                          found (%)    62.75       4.91   8.52                                          ______________________________________                                    

EXAMPLE 34N-Cyclohexyl-N-methyl-4-{N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide##STR172##

m.p. (°C.): 247˜250 (AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.70 (1H, s), 8.30 (2H, d, J=8.8 Hz), 7.91(2H, d, J=8.8 Hz), 7.91 (2H, d, J=8.8 Hz), 7.76 (2H, d, J=8.8 Hz), 7.75(1H, d, J=15.8 Hz), 7.00 (1H, d, J=15.8 Hz), 3.6 (1H, m), 2.67 (3H, s),1.8˜1.0 (10H, m)

Mass m/e (FD): 443 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.22 H.sub.25 N.sub.3 O.sub.5 S.0.25H.sub.2 O                  C         H      N                                                 ______________________________________                                        calculated (%)                                                                             58.97       5.74   9.38                                          found (%)    59.11       5.75   9.19                                          ______________________________________                                    

EXAMPLE 35N-Cyclohexyl-4-{N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide##STR173##

m.p. (°C.): 261˜262 (AcOEt-H₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.63 (1H, brs), 8.26 (2H, d, J=8.8 Hz),7.86 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.8 Hz), 7.71 (1H, d, J=16.2 Hz),7.49 (1H, d, J=7.9 Hz, D₂ O exchange), 6.98 (1H, d, J=16.2 Hz), 2.90(1H, m), 1.8˜1.0 (10H, m)

Mass m/e (FD): 429 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.21 H.sub.23 N.sub.3 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             58.73       5.40   9.78                                          found (%)    58.45       5.45   9.49                                          ______________________________________                                    

EXAMPLE 36N-Cyclohexyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide##STR174##

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.17 (2H, d, J=8.8 Hz), 7.88 (2H, d, J=8.8Hz), 7.73 (2H, d, J=8.8 Hz), 7.65 (1H, d, J=16.1 Hz), 7.55 (2H, d, J=8.8Hz), 6.70 (1H, d, J=16.1 Hz), 3.38 (3H, s), 2.96 (1H, m), 1.8˜1.0 (10H,m)

Mass m/e (FD): 443 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.22 H.sub.25 N.sub.3 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             59.58       5.68   9.48                                          found (%)    59.58       5.64   9.36                                          ______________________________________                                    

EXAMPLE 37N-Cyclohexyl-N-methyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide##STR175##

m.p. (°C.): 124˜125 (AcOEt-iso-Pr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.18 (2H, d, J=8.8 Hz), 7.87 (2H, d, J=8.8Hz), 7.74 (2H, d, J=8.8 Hz), 7.64 (1H, d, J=15.8 Hz), 7.56 (2H, d, J=8.8Hz), 6.70 (1H, d, J=15.8 Hz), 3.64 (1H, m), 3.39 (1H, s), 2.72 (3H, s),1.8˜1.0 (10H, m)

Mass m/e (FD): 457 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.23 H.sub.27 N.sub.3 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.38       5.95   9.18                                          found (%)    60.33       5.89   8.93                                          ______________________________________                                    

EXAMPLE 38N-cycloheptyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide##STR176##

m.p. (°C.): 187˜188 (AcOEt-iso-Pr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.19 (2H, d, J=8.6 Hz), 7.96 (2H, d, J=8.6Hz), 7.75 (1H, d, J=15.4 Hz), 7.46 (2H, d, J=8.6 Hz), 7.37 (2H, d, J=8.6Hz), 6.44 (1H, d, J=15.4 Hz), 4.51 (1H, brd, J=7.9 Hz), 3.47 (3H, s),3.4 (1H, m), 2.0˜1.2 (12H, m)

Mass m/e (FD): 457 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.23 H.sub.27 N.sub.3 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.38       5.95   9.18                                          found (%)    60.33       5.96   9.02                                          ______________________________________                                    

EXAMPLE 39 N-Cycloheptyl-4-{N-methyl-N-[(2E,4E)-5-(4-nitrophenyl)-2,4-pentadienoyl]amino}benzenesulfonamide##STR177##

m.p. (°C.): 208˜210 (AcOEt-iso-Pr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.13 (2H, d, J=8.8 Hz), 7.84 (2H, d, J=8.8Hz), 7.71 (2H, d, J=8.8 Hz), 7.67 (2H, d, J=7.2 Hz, D₂ O exchange), 7.49(2H, d, J=8.8 Hz), 7.4˜7.0 (3H, m), 6.13 (1H, m), 3.33 (1H, m), 3.22(3H, m), 2.0˜1.2 (12H, m)

Mass m/e (FD): 483 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.29 N.sub.3 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             62.09       6.05   8.69                                          found (%)    62.03       6.02   8.68                                          ______________________________________                                    

EXAMPLE 40N-(2-Indanyl-4-{N-methyl-N-[(E)-3-(3,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR178##

m.p. (°C.): 243˜244 (AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.36 (2H, s), 8.13 (1H, d, J=6.6 Hz), 7.93(2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.36 (1H, d, J=15.8 Hz), 7.11(4H, s), 6.33 (1H, d, J=15.8 Hz), 6.27 (3H, brs), 3.33 (3H, s), 3.02(2H, dd, J=16.0, 7.5 Hz), 2.73 (2H, dd, J=16.0 Hz)

Mass m/e (FD): 464 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.24 N.sub.2 O.sub.5 S.0.6H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             63.17       5.34   5.89                                          found (%)    63.15       5.67   4.93                                          ______________________________________                                    

EXAMPLE 41N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR179##

m.p. (°C.): 215˜217 (iso Pr₂ O-Et₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.88 (1H, s, D₂ O exchange), 8.08 (1H, d,J=7.0 Hz, D₂ O exchange), 7.91 (2H, d, J=8.8 Hz), 7.5 (2H, d, J=8.8 Hz),7.48 (1H, d, J=15.4 Hz), 7.29 (2H, d, J=8.8 Hz), 7.11 (4H, s), 6.69 (2H,d, J=8.4 Hz), 6.31 (1H, d, J=15.4 Hz), 3.94 (1H, m), 3.36 (3H, s),3.16˜2.52 (4H, m)

Mass m/e (FD): 449 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.24 N.sub.2 O.sub.4 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             66.96       5.39   6.25                                          found (%)    66.63       5.23   6.04                                          ______________________________________                                    

EXAMPLE 42 Disodium salt of4-{(E)-1-[N-methyl-N-[4-(2-indanyl)aminosulfonylphenyl]amino]-3-propenoyl}phenoxyaceticacid ##STR180##

m.p. (°C.): 223˜237 (EtOH-H₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.74 (2H, d, J=8.8 Hz), 7.45 (1H, d, J=15.4Hz), 7.24 (4H, ABq), 7.02 (4H, m), 6.73 (2H, d, J=8.3 Hz), 6.22 (1H, d,J=15.4 Hz), 4.13 (2H, s), 3.29 (3H, s), 3.72 (1H, m), 2.96˜2.35 (4H, m)

Mass m/e (FAB): 551 (MNa⁺, base), 529 (MH⁺), 207, 137, 115

    ______________________________________                                        elemental analysis as C.sub.27 H.sub.24 N.sub.2 O.sub.6 Na.sub.2.4.1H.sub.    2 O                                                                                      C         H      N                                                 ______________________________________                                        calculated (%)                                                                             51.94       5.20   4.49                                          found (%)    51.58       4.90   4.40                                          ______________________________________                                    

EXAMPLE 43N-Cycloheptyl-4-{N-methyl-N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR181##

m.p. (°C.): 190˜191 (AcOEt-iso Pr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.87 (2H, d, J=8.4 Hz), 7.68 (1H, d, J=7.9Hz), 7.52 (2H, d, J=8.4 Hz), 6.96 (1H, d, J=15.6 Hz), 7.5˜6.7 (3H, m),6.28 (1H, d, J=15.6 Hz), 3.34 (3H, s), 3.2 (3H, m), 1.8˜1.1 (12H, m)

Mass m/e (FD): 446 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.23 H.sub.27 FN.sub.2 O.sub.4 S                               C         H      N                                                 ______________________________________                                        calculated (%)                                                                             61.86       6.10   6.27                                          found (%)    61.73       6.04   6.13                                          ______________________________________                                    

EXAMPLE 44 N-Cycloheptyl-4-{N-methyl-N-[(2E;4E)-5-(3,5-dibromo-4-hydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide##STR182##

m.p. (°C.): 201˜202 (EtOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.87 (2H, d, J=8.3 Hz), 7.70 (2H, s), 7.69(1H, d, J=7.5 Hz), 7.51 (2H, d, J=8.3 Hz), 7.40˜7.00 (2H, m), 7.00˜6.80(2H, m), 5.97 (1H, d, J=14.1 Hz), 3.30 (3H, s), 1.80˜1.00 (12H, m)

Mass m/e (FAB): 613 (MH⁺), 331, 307, 289, 154 (base)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.28 Br.sub.2 N.sub.2 O.sub.4 S                       C         H      N                                                 ______________________________________                                        calculated (%)                                                                             49.03       4.61   4.57                                          found (%)    48.79       4.40   4.53                                          ______________________________________                                    

EXAMPLE 45N-Cycloheptyl-4-{N-methyl-N-[(E)-3-(4-fluorophenyl-2-propenoyl)amino}benzenesulfonamide##STR183##

m.p. (°C.): 168˜169 (AcOEt-isoPr₂ O)

¹ H-NMR (90 MHz, CDCl₃) δ: 7.94 (2H, d, J=8.6 Hz), 7.68 (1H, d, J=15.6Hz), 7.36 (2H, d, J=8.6 Hz), 7.31 (2H, dd, J=8.8, 5.3 Hz), 6.98 (2H,J=8.8 Hz), 6.24 (1H, d, J=15.6 Hz), 4.61 (1H, d, J=8.4 Hz), 3.44 (3H,s), 3.44 (1H), 2.0˜1.3 (12H, m)

Mass m/e (FD): 430 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.23 H.sub.27 FN.sub.2 O.sub.3 S                               C         H      N                                                 ______________________________________                                        calculated (%)                                                                             64.16       6.32   6.51                                          found (%)    64.15       6.28   6.40                                          ______________________________________                                    

EXAMPLE 46 N-(2-Indanyl)-4-{N-methyl-N-[(2E,4E)-5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide##STR184##

m.p. (°C.): 194˜197 (AcOEt-isoPr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.11 (1H, d, J=6.6 Hz, D₂ O exchange), 7.90(2H, d, J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz), 7.11 (4H, s), 6.87˜6.50 (4H,m), 5.98 (1H, d, J=15.4 Hz), 3.32 (3H, s), 3.20˜2.52 (4H, m)

Mass m/e (FD): 491 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.27 H.sub.26 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             64.52       5.48   5.57                                          found (%)    64.52       5.53   5.58                                          ______________________________________                                    

EXAMPLE 47N-[2-(1,2,3,4-Tetrahydro)naphthyl]-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR185##

m.p. (°C.): 277˜280 (isoPr₂ O-Etzo)

¹ H-H-NMR (90 MHz, DMSO-d₆) δ: 9.20 (1H, br, D₂ O exchange), 7.92 (2H,d, J=8.3 Hz), 7.90 (1H, br, D₂ O, exchange), 7.53 (2H, d, J=8.3 Hz),7.39 (1H, d, J=15.8 Hz), 7.10˜6.80 (4H, m), 6.80˜6.52 (3H, m), 6.19 (1H,d, J=15.8 Hz), 2.72 (4H, m), 2.00˜1.60 (2H, m)

3 Mass m/e (FD): 479 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.26 H.sub.26 N.sub.2l O.sub.5 S                               C         H      N                                                 ______________________________________                                        calculated (%)                                                                             65.25       5.48   5.85                                          found (%)    65.20       5.51   5.64                                          ______________________________________                                    

EXAMPLE 48 N-[2-(1,2,3,4-Tetrahydro)naphthyl]-4-{N-methyl-N-[(2E,4E)-5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide##STR186##

m.p. (°C.): 190˜194 (isoPr₂ O-Et₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.91 (2H, d, J=8.4 Hz), 7.90 (1H, d, D₂ Oexchange), 7.51 (2H, d, J=8.8 Hz), 7.37˜6.59 (10H, m), 5.96 (1H, d,J=14.5 Hz), 3.32 (3H, s), 2.72 (4H, m), 1.77 (2H, m)

Mass m/e (FAB): 505 (MH⁺), 189, 131 (base)

    ______________________________________                                        elemental analysis as C.sub.28 H.sub.27 N.sub.2 O.sub.5 S.0.5H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             65.48       5.69   5.45                                          found (%)    65.37       5.88   5.25                                          ______________________________________                                    

EXAMPLE 49N-Cycloheptyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR187##

m.p. (°C.): 207˜210 (AcOEt-Et₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.86 (2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.8Hz), 7.37 (2H, d, J=15.4 Hz), 6.82˜6.59 (3H, m), 6.13 (1H, d, J=15.4Hz), 3.32 (3H, s), 1.90˜1.00 (12H, m)

Mass m/e (FD): 444 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.23 H.sub.28 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             62.14       6.35   6.30                                          found (%)    61.99       6.27   6.17                                          ______________________________________                                    

EXAMPLE 50 N-Cycloheptyl-4-{N-methyl-N-[(2E,4E)-5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide##STR188##

m.p. (°C.): 213˜215 (AcOEt-Et₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.30, 8.36 (each 1H, s, D₂ O exchange),7.85 (2H, d, J=8.4 Hz), 7.68 (1H, d, J=7.4 Hz, D₂ O exchange), 7.49 (2H,d, J=8.8 Hz), 7.33˜6.39 (6H, m), 5.89 (1H, d, J=14.1 Hz), 3.29 (3H, s),3.20 (1H, m), 1.44 (12H, m)

Mass m/e (FD): 470 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.30 N.sub.2 O.sub.5 S.0.5H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             62.61       6.52   5.84                                          found (%)    62.54       6.37   5.66                                          ______________________________________                                    

EXAMPLE 51N-(2-Indanyl)-4-{N-methyl-N-I(E)-3-(2-chloro-3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR189##

m.p. (°C.): 201˜205 (isoPr₂ O-AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.25, 8.00 (each 1H, br, D₂ O exchange),7.92 (2H, d, J=8.3 Hz), 7.78 (1H, d, J=15.4 Hz), 7.57 (2H, d, J=8.3 Hz),7.10 (4H, s), 6.86 (1H, d, J=8.0 Hz), 6.64 (1H, d, J=8.0 Hz), 6.37 (1H,d, J=15.4 Hz), 3.37 (3H, s), 3.20˜2.52 (4H, m)

Mass m/e (FD): 498 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.23 ClN.sub.2 O.sub.5 S                              C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.18       4.65   5.61                                          found (%)    60.24       4.81   5.62                                          ______________________________________                                    

EXAMPLE 52N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(3-chloro-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR190##

m.p. (°C.): 234˜235 (AcOEt-CH₂ Cl₂ -EtOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.00˜9.00, 8.00 (each 1H, br, D₂ Oexchange), 7.91 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.38 (1H, d,J=15.8 Hz), 7.09 (4H, s) 6.98 (1H, brs), 6.79 (1H, brs), 6.29 (1H, d,J=15.4 Hz), 3.92 (1H, br), 3.35 (3H, s), 3.16˜2.55 (4H, m)

Mass m/e (FD): 498 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.23 ClN.sub.2 O.sub.5 S                              C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.18       4.65   5.61                                          found (%)    59.88       4.76   5.52                                          ______________________________________                                    

EXAMPLE 53N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(2-chloro-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR191##

m.p. (°C.): 226˜228 (AcOEt-CH₂ Cl₂)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.12 (1H, d, J=6.1 Hz, D₂ O exchange), 7.92(2H, d, J=8.4 Hz), 7.74 (1H, d, J=15.4 Hz), 7.57 (2H, d, J=8.8 Hz), 7.10(4H, s), 6.85 (1H, s), 6.80 (1H, s), 6.30 (1H, d, J=15.4 Hz), 3.94 (1H,m), 3.36 (3H, s), 3.20˜2.54 (4H, m)

Mass m/e (FD): 498 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.23 ClN.sub.2 O.sub.5 S.H.sub.2 O                    C         H      N                                                 ______________________________________                                        calculated (%)                                                                             58.09       4.87   5.42                                          found (%)    58.20       4.70   5.36                                          ______________________________________                                    

EXAMPLE 54N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(3-bromo-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR192##

m.p. (°C.): 221˜222 (MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.90, 9.55 (each 1H, br, D₂ O exchange),8.11 (1H, d, J=6.4 Hz, D₂ O exchange), 7.92 (2H, d, J=8.8 Hz), 7.56 (2H,d, J=8.8 Hz), 7.39 (1H, d, J=15.4 Hz), 7.10 (4H, s), 7.10 (1H, s), 6.82(1H, d, J=2 Hz), 6.29 (1H, d, J=15.4 Hz), 3.92 (1H, m), 3.36 (3H, s),3.20˜2.56 (4H, m)

Mass m/e (FD): 543 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.23 BrN.sub.2 O.sub.5 S                              C         H      N                                                 ______________________________________                                        calculated (%)                                                                             55.25       4.27   5.16                                          found (%)    55.15       4.32   4.75                                          ______________________________________                                    

EXAMPLE 55N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(2-bromo-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR193##

m.p. (°C.): 231˜233 (AcOEt-MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.56 (2H, brs), 8.08 (1H, brd, J=6 Hz),7.93 (2H, d, J=8.6 Hz), 7.71 (1H, d, J=14.3 Hz), 7.58 (2H, d, J=8.6 Hz),7.11 (4H, s), 6.97 (1H, s), 6.86 (1H, s), 6.26 (1H, d, J=14.3 Hz), 3.92(1H, brq, J=7 Hz), 3.34 (3H, s), 3.01 (2H, dd, J=15.8, 7.0 Hz), 2.72(2H, dd, J=15.8, 7.0 Hz)

Mass m/e (FAB): 544, 542 (M⁺); 243, 241, 162 (base); 117

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.23 BrN.sub.2 O.sub.5 S                              C         H      N                                                 ______________________________________                                        calculated (%)                                                                             55.25       4.27   5.16                                          found (%)    54.95       4.33   4.96                                          ______________________________________                                    

EXAMPLE 56N-(2-indanyl)-4-{N-methyl-N-I(E)-3-(3,4-dihydroxyphenyl)-2-methyl-2-propenoyl]amino}benzenesulfonamide##STR194##

m.p. (°C.): 155˜156 (isoPr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.98 (2H, br, D₂ O exchange), 7.96 (1H, br,D₂ O exchange), 7.80 (2H, d, J=8.4 Hz), 7.47 (2H, d, J=8.8 Hz), 7.03(4H, m), 6.73˜6.31 (4H, m), 3.80 (1H, m), 3.34 (3H, s), 3.04˜2.44 (4H,m), 1.83 (3H, s)

Mass m/e (FAB): 479 (MH⁺), 282, 177 (base), 149, 131

    ______________________________________                                        elemental analysis as C.sub.26 H.sub.26 ClN.sub.2 O.sub.5 S                              C         H      N                                                 ______________________________________                                        calculated (%)                                                                             65.25       5.48   5.85                                          found (%)    65.09       5.54   5.74                                          ______________________________________                                    

EXAMPLE 57N-Cyclopentyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR195##

m.p. (°C.): 209˜211 (AcOEt-Et₂ o)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.10 (1H, br, D₂ O exchange), 7.87 (2H, d,J=8.8 Hz), 7.52 (2H, d, J=8.4 Hz), 7.38 (2H, d, J=15.4 Hz), 6.82˜6.60(3H, m), 6.13 (1H, d, J=15.3 Hz), 3.32 (3H, s), 3.10˜3.60 (1H, m),1.90˜1.10 (8H, m)

Mass m/e (FD):

416 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.21 H.sub.24 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.56       5.81   6.73                                          found (%)    60.56       5.91   6.46                                          ______________________________________                                    

EXAMPLE 58N-Cyclohexyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR196##

m.p. (°C.): 224˜225 (AcOEt-isoPr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.16 (2H, brs), 7.88 (2H, d, J=8.6 Hz),7.64 (1H, brd, J=7 Hz), 7.52 (2H, d, J=8.6 Hz), 7.38 (2H, d, J=15.9 Hz),6.77 (1H, brs), 6.69 (2H, s), 6.13 (1H, d, J=15.9 Hz), 3.34 (3H, s),3.00 (1H, m), 1.8˜1.0 (10H, m)

Mass m/e (FD): 430 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.22 H.sub.26 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             61.38       6.09   6.51                                          found (%)    61.19       6.17   6.11                                          ______________________________________                                    

EXAMPLE 59N-(1-Indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR197##

m.p. (°C.): 202˜206 (isoPr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.10, 8.15 (each 1H, br, D₂ O exchange),7.95 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.3 Hz), 7.39 (1H, d, J=15.4 Hz),7.82˜7.57 (3H, m), 7.23˜7.05 (4H, m), 6.19 (1H, d, J=15.4 Hz), 4.62 (1H,m), 3.34 (3H, s), 2.72 (2H, m), 2.30˜1.40 (2H, m)

Mass m/e (FD): 465 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.24 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             64.64       5.21   6.03                                          found (%)    64.69       5.32   6.05                                          ______________________________________                                    

EXAMPLE 60N-[2-(2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR198##

m.p. (°C.): 95˜105 (amorphous, isoPr₂ O-Et₂ O -AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.39, 9.07 (each 1H, s, D₂ O exchange),8.44 (1H, m), 7.83 (2H, d, J=8.3 Hz), 7.51 (2H, d, J=8.4 Hz), 7.70˜7.40(1H, m), 7.30˜7.05 (3H, m), 6.80˜6.50 (3H, m), 6.19 (1H, d, J=15.4 Hz),3.32 (3H, s), 3.40˜2.60 (4H, m)

Mass m/e (FD): 454 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.23 H.sub.23 N.sub.3 O.sub.5 S.0.3H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.12       5.19   9.14                                          found (%)    60.15       5.36   8.90                                          ______________________________________                                    

EXAMPLE 61 N-(2-Thiazolyl)-4-{N-I(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR199##

m.p. (°C.): 219˜220 (MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.37, 9.49, 9.21 (each 1H, brs, D₂ Oexchange), 7.78 (4H, s), 7.44 (1H, d, J=16.2 Hz), 7.24 (2H, d, J=4.8Hz), 7.03˜6.67 (3H, m), 6.80 (1H, d, J=4.8 Hz), 6.52 (1H, d, J=16.2 Hz)

Mass m/e (FD): 417 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.18 H.sub.15 N.sub.3 O.sub.5 S.sub.2                          C         H      N                                                 ______________________________________                                        calculated (%)                                                                             51.79       3.62   10.07                                         found (%)    51.39       3.61   10.03                                         ______________________________________                                    

EXAMPLE 62N-[2-(4,6-Dimethyl)pyrimidyl]-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR200##

m.p. (°C.): 174˜177 (MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.56 (1H, brs, D₂ O exchange), 7.96 (2H,d, J=8.8 Hz), 7.81 (1H, d, J=8.8 Hz), 7.45 (1H, d, J=15.7 Hz), 7.09˜6.71(4H, m), 6.57 (1H, d, J=15.7 Hz), 2.27 (6H, s)

Mass m/e (FD): 440 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.21 H.sub.20 N.sub.4 O.sub.5 S.3H.sub.2 O                     C         H      N                                                 ______________________________________                                        calculated (%)                                                                             51.01       5.30   11.32                                         found (%)    50.86       4.70   10.99                                         ______________________________________                                    

EXAMPLE 63N-(2-Hydroxyethyl)-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR201##

m.p. (°C.): 216˜219 (MeOH-H₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.41 (1H, s), 9.60˜9.00 (2H, br, D₂ Oexchange), 7.79 (4H, ABq), 7.60˜7.36 (2H, m), 7.09˜6.68 (3H, m), 6.72(1H, d, J=16.3 Hz), 3.36 (2H, t, J=6.6 Hz), 2.78 (2H, q like, J=6.2 Hz)

Mass m/e (FD): 378 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.17 H.sub.8 N.sub.2 O.sub.6 S                                 C         H      N                                                 ______________________________________                                        calculated (%)                                                                             53.96       4.80   7.40                                          found (%)    53.91       4.81   7.02                                          ______________________________________                                    

EXAMPLE 64N-Cyclohexyl-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR202##

m.p. (°C.): 120˜124 (AcOEt-isoPr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.39 (1H, s), 9.49 (1H, s), 9.20 (1H, s),7.87 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.8 Hz), 7.50 (1H, d, J=7.9 Hz),7.46 (1H, d, J=15.4 Hz), 7.02 (1H, brs), 6.96 (1H, brd, J=7.9 Hz), 6.77(1H, d, J=7.9 Hz), 6.54 (1H, d, J=15.4 Hz), 2.91 (1H, m), 1.8˜1.1 (10H,m)

Mass m/e (FD): 416 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.21 H.sub.24 N.sub.2 O.sub.5 S.0.3H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             59.78       5.88   6.64                                          found (%)    60.06       5.91   6.12                                          ______________________________________                                    

EXAMPLE 654-{N-Methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR203##

m.p. (°C.): 205˜206 (AcOEt-Et₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.38 (1H, brs, D₂ O exchange), 9.07 (1H,brs, D₂ O exchange), 7.86 (2H, d, J=8.3 Hz), 7.48 (2H, d, J=8.3 Hz),7.37 (2H, d, J=15.4 Hz), 7.40 (2H, s, D₂ O exchange), 6.69 (3H, m), 6.16(1H, d, J=15.4 Hz), 3.29 (3H, s)

Mass m/e (FD): 348 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.16 H.sub.16 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             55.16       4.63   8.04                                          found (%)    55.06       4.68   7.64                                          ______________________________________                                    

EXAMPLE 664-{N-Isopropyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR204##

m.p. (°C.): 224˜228 (H₂ O-MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.20 (1H, br, D₂ O exchange), 7.94 (2H, d,J=7.9 Hz), 7.80˜7.20 (1H, br, D₂ O exchange), 7.44 (2H, d, J=7.9 Hz),7.39 (1H, d, J=15.4 Hz), 6.67 (3H, s), 5.80 (1H, d, J=15.4 Hz), 4.92(1H, m), 1.05 (6H, d, J=6.5 Hz)

Mass m/e (FD): 376 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.18 H.sub.20 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             57.43       5.36   7.44                                          found (%)    57.38       5.36   7.30                                          ______________________________________                                    

EXAMPLE 67N-[2-(N,N-Dimethylamino)ethyl]-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamidehydrochloride ##STR205##

m.p. (°C.): 177˜180 (AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.40 (1H, br, D₂ O exchange), 9.6˜8.8,8.22 (each 1H, br, D₂ O exchange), 7.92 (2H, d, J=8.3 Hz), 7.56 (2H, d,J=8.3 Hz), 7.43 (1H, d, J=15.4 Hz), 6.92˜6.64 (3H, m), 6.22 (1H, d,J=15.4 Hz), 3.34 (3H, s), 3.17 (4H, brs), 2.76 (6H, s)

Mass m/e (FD): 420 (MH⁺)

    ______________________________________                                        elemental analysis as C.sub.20 H.sub.25 N.sub.3 O.sub.5 S.HCl.0.3H.sub.2                 C         H      N                                                 ______________________________________                                        calculated (%)                                                                             52.07       5.81   9.11                                          found (%)    52.13       5.66   8.88                                          ______________________________________                                    

EXAMPLE 68N-methyl-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR206##

m.p. (°C.): 180˜182 (Et₂ O -AcOEt-EtOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.20 (2H, br, D₂ O exchange), 7.85 (2H, d,J=8.4 Hz), 7.54 (2H, d, J=8.3 Hz), 7.40 (1H, d, J=15.3 Hz), 6.84˜6.60(3H, m), 6.21 (1H, d, J=15.3 Hz), 3.34 (3H, s), 2.47 (3H, s, D₂ Osharpen)

Mass m/e (FD): 362 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.17 H.sub.18 N.sub.2 O.sub.5 S.0.1H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             56.06       5.04   7.69                                          found (%)    56.28       5.06   7.30                                          ______________________________________                                    

EXAMPLE 69N-Isopropyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR207##

m.p. (°C.): 197˜199 (H₂ O-MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.50˜8.50 (1H, br), 7.87 (2H, d, J=8.8Hz), 7.70˜7.24 (4H, m), 6.80˜6.60 (3H, m), 6.13 (1H, d, J=15.3 Hz), 3.32(3H, s), 0.98 (6H, d, J=7.0 Hz)

Mass m/e (FAB): 391 (MH⁺), 289, 228, 236

    ______________________________________                                        elemental analysis as C.sub.19 H.sub.22 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             58.45       5.68   7.18                                          found (%)    58.33       5.64   6.98                                          ______________________________________                                    

EXAMPLE 70(E)-N-Methyl-N-[4-(4-morpholinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide##STR208##

m.p. (°C.): 265˜266 (THF-MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.40, 9.03 (each 1H, br, D₂ O exchange),7.81 (2H, d, J=8.4 Hz), 7.59 (2H, d, J=8.8 Hz), 7.40 (1H, d, J=15.4 Hz),6.86˜6.60 (3H, m), 6.22 (1H, d, J=15.4 Hz), 3.65 (4H, m), 3.36 (3H, s),2.91 (4H, m)

Mass m/e (FD): 418 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.20 H.sub.22 N.sub.2 O.sub.6 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             57.40       5.30   6.70                                          found (%)    57.24       5.37   6.52                                          ______________________________________                                    

EXAMPLE 714-{N-[(E)-3-(3,4-Dimethoxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR209##

m.p. (°C.): 251˜2.52 (CH₂ Cl₂)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.40 (1H, br, D₂ O exchange), 7.82 (4H,s), 7.59 (1H, d, J=16.2 Hz), 7.24 (2H, brs, D₂ O exchange), 7.35˜7.11(2H, m), 7.01 (1H, d, J=8.1 Hz), 6.70 (1H, d, J=16.2 Hz), 3.34 (6H, s)

Mass m/e (FD): 362 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.17 H.sub.18 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             56.34       5.01   7.73                                          found (%)    56.27       4.94   7.56                                          ______________________________________                                    

EXAMPLE 724-{N-[(Z)-3-(3,4-Dimethoxyphenyl)-3-(3-Pyridyl)-2-propenoyl]amino}benzenesulfonamide##STR210##

m.p. (°C.): 168˜171 (CH₂ Cl₂ -EtOH-MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.69 (1H, brs), 8.68 (1H, m), 8.59 (1H,brs), 7.88 (1H, dt, J=7.9, 2.2 Hz), 7.71 (4H, s), 7.22 (2H, brs, D₂ Oexchange), 7.09 (1H, d, J=1.7 Hz), 7.01 (1H, d, J=8.4 Hz), 6.91 (1H, s),6.76˜6.52 (1H, m), 6.62 (1H, dd, J=8.4, 1.7 Hz), 3.78 (6H, s)

Mass m/e (FD): 439 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.22 H.sub.21 N.sub.3 O.sub.5 S.1.7H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             56.21       5.23   8.94                                          found (%)    55.84       4.67   8.70                                          ______________________________________                                    

EXAMPLE 734-{N-[(E)-3-(3,4-Dimethoxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide##STR211##

m.p. (°C.): 207˜208 (CH₂ Cl₂)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10-43 (1H, s, D₂ O exchange), 8.49˜8.63(2H, m), 7.71 (4H, s), 7.64 (1H, dt, J=7.9, 2.2 Hz), 7.41 (1H, dd,J=7.9, 3.9 Hz), 7.22 (2H, s, D₂ O exchange), 6.96 (1H, d, J=8.3 Hz),6.82 (1H, d, J=1.7 Hz), 6.71 (1H, dd, J=8.3, 1.8 Hz), 6.62 (1H, s),3.77, 3.63 (each 3H, s)

Mass m/e (FAB): 440 (MH⁺), 397, 289, 268

    ______________________________________                                        elemental analysis as C.sub.22 H.sub.21 N.sub.3 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.13       4.82   9.56                                          found (%)    60.15       4.77   9.36                                          ______________________________________                                    

EXAMPLE 744-{N-[(Z)-3-(3,4-Dihydroxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamidehydrobromide ##STR212##

m.p. (°C.): 255˜256 (EtOH-MeOH-H₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.41 (1H, brs, D₂ O exchange), 9.40, 9.11(each 1H, s, D₂ O exchange), 8.51 (2H, dd, J=4.9, 1.8 Hz), 8.33 (1H,brd, J=1.8 Hz), 7.69 (4H, s), 7.55 (1H, d, J=7.9 Hz), 7.38 (1H, dd,J=7.9, 4.9 Hz), 7.21 (2H, s, D₂ O exchange), 6.94˜6.52 (4H, m)

Mass m/e (FAB): 412 (MH⁺), 307, 289, 240

    ______________________________________                                        elemental analysis as C.sub.20 H.sub.17 N.sub.3 O.sub.5 S.HBr.0.7H.sub.2                 C         H      N                                                 ______________________________________                                        calculated (%)                                                                             47.57       3.84   8.32                                          found (%)    47.65       4.03   7.61                                          ______________________________________                                    

EXAMPLE 754-{N-[(E)-3-(3,4-Dihydroxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide##STR213##

m.p. (°C.): 195˜201 (CH₂ Cl₂ --H₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.37 (1H, brs, D₂ O exchange), 10.00 (1H,br, D₂ O exchange), 8.72˜8.48 (2H, m), 7.82˜7.60 (1H, m), 7.70 (4H, s),7.45 (1H, dd, J=7.9, 3.9 Hz), 7.21 (2H, s, D₂ O exchange), 6.70 (1H, d,J=7.9 Hz), 6.61 (1H, d, J=1.8 Hz), 6.49 (1H, s), 6.45 (1H, dd, J=7.9,1.8 Hz)

Mass m/e (FD): 411 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.20 H.sub.17 N.sub.3 O.sub.5 S.1.5H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             54.79       4.60   9.58                                          found (%)    54.90       4.18   8.96                                          ______________________________________                                    

EXAMPLE 764-{N-[(Z)-3-(3,4-Dihydroxyphenyl)-2-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamidehydrobromide ##STR214##

m.p. (°C.): 233˜235 (MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.30 (1H, s), 8.89 (2H, m), 8.35 (1H, brd,J=8.0 Hz), 8.01 (1H, dd, J=8.0, 4.8 Hz), 7.80 (4H, s), 7.71 (1H, s),7.29 (1H, br, D₂ O exchange), 6.67 (1H, d, J=8.8 Hz), 6.42 (1H, brs),6.50 (1H, dd, J=8.8, 1.5 Hz)

Mass m/e (FD): 411 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.20 H.sub.17 N.sub.3 O.sub.5 S.HBr.0.3H.sub.2                 C         H      N                                                 ______________________________________                                        calculated (%)                                                                             48.26       3.78   8.44                                          found (%)    48.45       3.94   7.86                                          ______________________________________                                    

EXAMPLE 774-{N-[(E)-3-(3,4-Dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR215##

m.p. (°C.): 292˜294 (MeOH-H₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.26 (2H, br, D₂ O exchange), 7.78 (4H, s),7.44 (1H, d, J=16.2 Hz), 7.20 (3H, br, D₂ O exchange), 7.10˜6.60 (3H,m), 6.51 (1H, d, J=16.2 Hz)

Mass m/e (FD): 334 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.15 H.sub.14 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             53.89       4.22   8.38                                          found (%)    53.64       4.13   8.15                                          ______________________________________                                    

EXAMPLE 78N-[4-(1-Piperidylmethyl)-benzyl]-4-{N-methyl-N-[(E)-3-(4-methylpulfonylphenyl)-2-propenoyl]amino}benzenesulfonamidehydrochloride ##STR216##

m.p. (°C.): 162˜164 (AcOEt-EtOH-MeOH)

¹ H-NMR (400 MHz, CDCl₃) δ: 11.30 (1H, brs), 8.12 (2H, d, J=8.2 Hz),7.88 (2H, d, J=8.1 Hz), 7.74 (2H, d, J=15.5 Hz), 7.70 (1H, t, J=6.3 Hz),7.55 (2H, d, J=8.4 Hz), 7.54 (1H, d, J=8.1 Hz), 7.40 (2H, d, J=8.2 Hz),7.39 (2H, d, J=7.7 Hz), 6.50 (1H, d, J=15.5 Hz), 4.15 (2H, d, J=6.3 Hz),4.03 (2H, d, J=5.1 Hz), 3.47 (3H, s), 3.41 (2H, d, J=10.8 Hz), 3.05 (3H,s), 2.61 (2H, q, J=10 Hz), 2.15 (2H, q, J=10 Hz), 1.79 (3H, m), 1.36(1H, q, J=10 Hz)

Mass m/e (FAB): 582 (MH⁺), 372, 203

    ______________________________________                                        elemental analysis as C.sub.30 H.sub.35 N.sub.3 O.sub.5 S.sub.2.HCl                      C         H      N                                                 ______________________________________                                        calculated (%)                                                                             58.28       5.87   6.80                                          found (%)    57.92       5.79   6.67                                          ______________________________________                                    

EXAMPLE 79[1-[2-(3,4-Dimethoxyphenyl)ethyl]-4-piperidyl]-4{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide##STR217##

m.p. (°C.): 146˜150 (Et₂ O-AcOEt)

¹ H-NMR (90 MHz, CDCl₃) δ: 7.98 (2H, d, J=8.6 Hz), 7.89 (2H, d, J=8.4Hz), 7.74 (1H, d, J=15.6 Hz), 7.51 (2H, d, J=8.4 Hz), 7.38 (2H, d, J=8.6Hz), 6.81˜6.70 (3H, m), 6.47 (1H, d, J=15.6 Hz), 4.88 (1H, brd), 3.85(3H, s), 3.84 (3H, s), 3.47 (3H, s), 3.32 (1H, m), 3.02 (3H, s), 2.82(2H, m), 2.75 (2H, m), 2.60 (2H, t, like), 2.09 (2H, m), 1.90 (2H, m),1.62 (2H, m)

Mass m/e (FAB): 642 (MH⁺), 490, 265, 264, 209, 165 (base)

    ______________________________________                                        elemental analysis as C.sub.32 H.sub.39 N.sub.3 O.sub.7 S.0.5H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             59.06       6.19   6.46                                          found (%)    58.94       6.04   6.06                                          ______________________________________                                    

EXAMPLE 80N-[1-[2-(3-Pyridyl)ethyl]-4-piperidyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamidehydrochloride ##STR218##

m.p. (°C.): 182˜185 (AcOEt)

¹ H-NMR (400 MHz, DMSO-d₆) δ: 8.46 (2H, brd), 8.00 (1H, m), 7.88 (4H, d,J=8.2 Hz), 7.77˜7.63 (3H, m), 7.62˜7.50 (3H, m), 7.35 (1H, brd), 6.70(1H, brd, J=15 Hz), 3.37 (3H, s), 3.19 (3H, s), 3.35˜2.85 (9H, m), 1.78(4H, m)

Mass m/e (FAB): 583 (MH⁺, 490, 277, 185 (base), 106

    ______________________________________                                        elemental analysis as C.sub.29 H.sub.35 N.sub.4 O.sub.5 S.sub.2.HCl.H.sub.    2 O                                                                                      C         H      N                                                 ______________________________________                                        calculated (%)                                                                             54.66       5.85   8.79                                          found (%)    54.76       5.76   8.99                                          ______________________________________                                    

EXAMPLE 81N-[1-[2-(6-Methyl-2-pyridyl)ethyl]-4-piperidyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]aminolbenzenesulfonamide##STR219##

m.p. (°C.): 161˜162 (Et₂ O -AcOEt)

¹ H-NMR (400 MHz, CDCl₃) δ: 7.96 (2H, d, J=8.6 Hz), 7.88 (2H, d, J=8.4Hz), 7.74 (1H, d, J=15.4 Hz), 7.50 (2H, d, J=8.4 Hz), 7.46 (1H, t, J=8.0Hz), 7.37 (2H, d, J=8.6 Hz), 6.95 (2H, d, J=8.2 Hz), 6.47 (1H, d, J=15.4Hz), 4.72 (1H, brd), 3.46 (3H, s), 3.30 (1H, m), 3.02 (3H, s), 2.70 (4H,m), 2.49 (3H, s), 2.18 (2H, t, J=7.0 Hz), 1.85 (2H, m), 1.56 (2H, m)

Mass m/e (FAB): 597 (MH⁺), 490, 282, 201 (base), 175

    ______________________________________                                        elemental analysis as C.sub.30 H.sub.36 N.sub.4 O.sub.5 S.sub.2                          C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.38       6.08   9.39                                          found (%)    60.09       6.01   9.25                                          ______________________________________                                    

EXAMPLE 82N-[4-[1-pyrrolidylmethyl)benzyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide##STR220##

m.p. (°C.): 180˜182 (AcOEt-CH₂ Cl₂)

¹ H-NMR (400 MHz, CDCl₃) δ: 7.94 (2H, d, J=8.8 Hz), 7.87 (2H, d, J=8.2Hz), 7.74 (1H, d, J=15.4 Hz), 7.51 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=8.8Hz), 7.26 (2H, d, J=8.2 Hz), 7.16 (2H, d, J=8.2 Hz), 6.47 (1H, d, J=15.4Hz), 4.20 (2H, s), 3.58 (2H, s), 3.46 (3H, s), 3.03 (3H, s), 2.49 (4H,brs), 1.77 (4H, m)

Mass m/e (FAB): 568 (MH⁺), 358, 314, 209, 119 (base)

    ______________________________________                                        elemental analysis as C.sub.29 H.sub.33 N.sub.3 O.sub.5 S.sub.2.0.7H.sub.2     O                                                                                       C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.02       5.98   7.24                                          found (%)    59.97       5.73   7.08                                          ______________________________________                                    

EXAMPLE 83N-[8-(5,6,7,8-Tetrahydro)quinolyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamidehydrochloride ##STR221##

m.p. (°C.): 147˜150 (AcOEt-MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 8.62 (1H, d, J=6 Hz), 8.55 (1H, brs), 8.13(1H, d, J=8 Hz), 7.98 (2H, d, J=8.8 Hz), 7.88˜7.60 (6H, m), 7.58 (2H, d,J=8.8 Hz), 6.69 (1H, d, J=15.8 Hz), 4.78 (1H, m), 3.39 (3H, s), 3.20(3H, s), 2.80 (2H, m), 1.70 (4H, m)

Mass m/e (FD): 525 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.26 H.sub.27 N.sub.5 O.sub.5 S.sub.2.HCl.1.5H.s    ub.2 O                                                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             53.01       5.30   7.13                                          found (%)    52.64       5.08   7.07                                          ______________________________________                                    

EXAMPLE 84N-Cyclohexyl-4-{N-[(E)-3-(3-fluoro-4-hydroxyphenyl-2-propenoyl]}aminobenzenesulfonamide##STR222##

m.p. (°C.): 148˜150 (AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.38 (2H, brs), 7.82 (2H, d, J=8.8 Hz),7.69 (2H, d, J=8.8 Hz), 7.6˜6.9 (4H, m), 6.61 (1H, d, J=15.1 Hz), 2.9(1H, m), 1.8˜0.9 (10H, m)

Mass m/e (FD): 418 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.21 H.sub.23 FN.sub.2 O.sub.5 S                               C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.27       5.54   6.69                                          found (%)    60.27       5.61   6.50                                          ______________________________________                                    

EXAMPLE 85N-Cyclohexyl-N-methyl-4-{N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR223##

m.p. (°C.): 115˜120 (AcOEt-isoPr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.42 (2H, brs), 7.85 (2H, d, J=8.8 Hz),7.70 (2H, d, J=8.8 Hz), 7.6˜6.8 (3H, m), 7.33 (1H, d, J=15.1 Hz), 6.62(1H, d, J=15.1 Hz), 3.6 (1H, m), 2.68 (3H, s), 1.8˜1.0 (10H, m)

Mass m/e (FD): 432 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.22 H.sub.25 FN.sub.2 O.sub.4 S                               C         H      N                                                 ______________________________________                                        calculated (%)                                                                             61.09       5.83   6.48                                          found (%)    60.89       5.98   6.24                                          ______________________________________                                    

EXAMPLE 86N-Cycloheptyl-4-{N-methyl-N-[(E)-3-(4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR224##

m.p. (°C.): 187˜189 (AcOEt-isoPr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.80 (1H, br, D₂ O exchange), 7.87 (2H, d,J=8.3 Hz), 7.68 (1H, d, J=7.5 Hz, D₂ O exchange), 7.52 (2H, d, J=8.3Hz), 7.46 (1H, d, J=15.4 Hz), 7.23 (2H, d, J=8.8 Hz), 6.70 (2H, d, J=8.4Hz), 6.20 (1H, d, J=15.4 Hz), 3.33 (3H, s), 3.16 (1H, s), 3.33 (3H, s),1.80˜1.00 (12H, m)

Mass m/e (FAB): 429 (MH⁺), 309, 253, 147 (base), 107

    ______________________________________                                        elemental analysis as C.sub.23 H.sub.28 N.sub.2 O.sub.4 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             64.46       6.59   6.54                                          found (%)    64.38       6.70   6.36                                          ______________________________________                                    

EXAMPLE 87N-Cyclooctyl-4-{N-methyl-N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR225##

m.p. (°C.): 190˜191 (isoPr₂ O-AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.87 (2H, d, J=8.7 Hz), 7.67 (1H, d, J=7.7Hz, D₂ O exchange), 7.51 (2H, d, J=8.8 Hz), 7.44 (1H, d, J=15.4 Hz),7.35˜6.85 (3H, m), 6.27 (1H, d, J=15.4 Hz), 3.33 (3H, s), 2.84˜1.05(14H, m)

Mass m/e (FAB): 461 (MH⁺, base), 351, 271, 165, 137

    ______________________________________                                        elemental analysis as C.sub.24 H.sub.29 FN.sub.2 O.sub.4 S                               C         H      N                                                 ______________________________________                                        calculated (%)                                                                             62.59       6.35   6.08                                          found (%)    62.52       6.17   6.03                                          ______________________________________                                    

EXAMPLE 88N-Cycloheptyl-4-{N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide##STR226##

m.p. (°C.): 178˜180 (isoPr₂ O-AcOEt)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.46 (1H, s, D₂ O exchange), 7.70 (4H,ABq), 7.59˜7.20 (5H, m), 6.90 (1H, t like, J=8.0 Hz), 6.66 (1H, d,J=15.4 Hz), 3.12 (1H, m), 1.80˜1.00 (12H, m)

Mass m/e (FAB): 433 (MH⁺, base), 337, 320, 257, 165, 112

    ______________________________________                                        elemental analysis as C.sub.22 H.sub.25 N.sub.2 O.sub.4 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             61.09       5.83   6.48                                          found (%)    60.96       5.73   6.34                                          ______________________________________                                    

EXAMPLE 894-{N-[(E)-3-(3-Acetoxy-4-methoxyphenyl)-2-propenoyl]amino}benzenesulfonamid##STR227##

m.p. (°C.): 237˜239 (AcOEt)

¹ H-NMR (400 MHz, DMSO-d₆) δ: 7.86 (1H, d, J=8.8 Hz), 7.79 (2H, d, J=8.8Hz), 7.63 (1H, d, J=15.7 Hz), 7.40 (1H, d, J=1.8 Hz), 7.26 (2H, m), 7.17(1H, d, J=7.9 Hz), 6.83 (1H, d, J=15.7 Hz), 3.84 (3H, s), 2.27 (3H, s)

Mass m/e (FAB): 391 (MH⁺), 349, 219, 177 (base), 145

    ______________________________________                                        elemental analysis as C.sub.18 H.sub.18 N.sub.2 O.sub.6 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             55.38       4.65   7.18                                          found (%)    55.46       4.58   6.94                                          ______________________________________                                    

EXAMPLE 90N-Cycloheptyl-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-methyl-2-propenoyl]amino}benzenesulfonamide##STR228##

m.p. (°C.): 206˜207 (Et₂ O -EtOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.26, 9.09 (each 1H, br, D₂ O exchange),7.46 (1H, d, J=6.6 Hz, D₂ O exchange), 7.18 (brs), 6.98˜6.70 (3H, m),3.08 (1H, m), 2.10 (3H, s), 1.82˜1.00 (12H, m)

Mass m/e (FAB): 445 (MH⁺), 349, 269, 177, 149, 131

    ______________________________________                                        elemental analysis as C.sub.23 H.sub.28 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             62.14       6.35   6.30                                          found (%)    61.99       6.41   6.20                                          ______________________________________                                    

EXAMPLE 91N-Cyclohexyl-4-{N-methyl-N-[(E)-3-(3,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR229##

m.p. (°C.): 240˜241 (AcOEt-isoPr₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.29 (2H, s), 7.84 (2H, d, J=8.6 Hz), 7.67(2H, d, J=7.9 Hz), 7.48 (2H, d, J=8.6 Hz), 7.28 (1H, d, J=15.5 Hz), 6.22(1H, d, J=15.5 Hz), 3.34 (3H, s), 2.99 (1H, m), 1.8˜1.0 (10H, m)

Mass m/e (FD): 430 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.22 H.sub.26 N.sub.2 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             61.38       6.09   6.51                                          found (%)    61.43       6.17   6.13                                          ______________________________________                                    

EXAMPLE 92N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(4-hydroxy-3methoxyphenyl)-2-cyano-2-propenoyl]amino}benzenesulfonamide##STR230##

m.p. (°C.): 185˜186 (MeOH-THF)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.19 (1H, br, D₂ O exchange), 8.07 (1H, d,J=7.5 Hz), 7.83 (2H, d, J=8.4 Hz), 7.83 (1H, d, J=8.4 Hz), 7.59 (2H, d,J=8.4 Hz), 7.59 (1H, d, J=8.4 Hz), 7.36 (1H, dd, J=8.2 Hz), 7.06 (4H,s), 6.84 (1H, d, J=8.4 Hz), 3.68 (3H, s), 3.40 (3H, s), 3.24˜2.50 (4H,m)

Mass m/e (FD): 503 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.27 H.sub.25 N.sub.3 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             64.40       5.00   8.35                                          found (%)    64.42       5.01   7.98                                          ______________________________________                                    

EXAMPLE 934-{N-[(E)-3-(3,4-Dihydroxyphenyl)-2-propenoyl]amino}-5,6,7,8-tetrahydro-1-naphthalenesulfonamide##STR231##

m.p. (°C.): 270˜272 (MeOH-H₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 9.58 (1H, br, D₂ O exchange), 9.29 (1H,brs, D₂ O exchange), 9.15 (1H, br, D₂ O exchange), 7.69 (2H, s), 7.42(1H, d, J=15.8 Hz), 7.30 (2H, s, D₂ O exchange), 7.08˜6.60 (4H, m), 3.15(2H, m), 2.71 (2H, m), 1.75 (4H, m)

Mass m/e (FD): 388 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.19 H.sub.20 N.sub.2 O.sub.5 S.0.4H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             57.68       5.30   7.08                                          found (%)    57.83       5.24   6.90                                          ______________________________________                                    

EXAMPLE 94N-Isopropyl-4-{N-methyl-N-[(E)-3-(2-chloro-3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR232##

m.p. (°C.): 247˜248 (CH₂ Cl₂ -Et₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.50˜8.50 (2H, br, D₂ O exchange), 7.86(2H, d, J=8.4 Hz), 7.76 (1H, d, J=15.4 Hz), 7.53 (2H, d, J=8.8 Hz), 6.78(1H, d, J=8.8 Hz), 6.63 (1H, d, J=8.8 Hz), 6.28 (1H, d, J=15.4 Hz), 3.34(3H, s), 3.20 (1H, m), 0.96 (6H, d, J=6.6 Hz)

Mass m/e (FD): 424 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.19 H.sub.21 ClN.sub.2 O.sub.5 S.0.2H.sub.2 O                 C         H      N                                                 ______________________________________                                        calculated (%)                                                                             53.26       5.03   6.54                                          found (%)    53.14       5.07   6.27                                          ______________________________________                                    

EXAMPLE 954-{N-[(E)-3-(2-Bromo-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR233##

m.p. (°C.): 271˜273 (MeOH-H₂ O)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.81 (4H, s), 7.80 (1H, br, D₂ O exchange),7.75 (1H, d, J=15.4 Hz), 7.20 (1H, br, DzO exchange), 7.14 (1H, s), 7.01(1H, s), 6.58 (1H, d, J=15.4 Hz)

Mass m/e (FD): 413 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.15 H.sub.13 BrN.sub.2 O.sub.5 S.0.25H.sub.2                  C         H      N                                                 ______________________________________                                        calculated (%)                                                                             43.13       3.26   6.71                                          found (%)    43.32       3.42   6.31                                          ______________________________________                                    

EXAMPLE 96N-(2-Thiazolyl)-4-{N-[(Z)-3-(3,4-dimethoxyphenyl)-2-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide##STR234##

m.p. (°C.): 220˜223 (EtOH-MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 10.22 (1H, brs), 8.52 (1H, dd, J=4.8, 1.8Hz), 8.35 (1H, d like, J=1.8 Hz), 7.75 (4H, m, ABq), 7.67 (1H, dt,J=8.0, 1.8 Hz), 7.53 (1H, s), 7.42 (1H, dd, J=8.0, 4.8 Hz), 7.20 (1H, d,J=4.8 Hz), 6.86 (1H, d, J=8.8 Hz), 6.77 (1H, d, J=4.8 Hz), 6.70 (1H,brd, J=8.8 Hz), 6.48 (1H, brs), 3.72 and 3.39 (each 3H, s)

Mass m/e (FD): 522 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.25 H.sub.22 N.sub.4 O.sub.5 S.sub.2.0.5H.sub.2     O                                                                                       C         H      N                                                 ______________________________________                                        calculated (%)                                                                             56.48       4.36   10.54                                         found (%)    56.74       4.26   10.57                                         ______________________________________                                    

EXAMPLE 974-{N-[(Z)-3-(3,4-Dimethoxyphenyl)-2-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide##STR235##

m.p. (°C.): 236˜237 (EtOH-MeOH)

¹ H-NMR (90 MHz, DMSO-d₆) δ 10.32 (1H, s), 8.64 (1H, m), 8.44 (1H, brs),7.80 (4H, m, ABq), 7.83˜7.65 (1H, m), 7.62 (1H, s), 7.53 (1H, dd, J=8.1,4.8 Hz), 7.27 (2H, s, D₂ O exchange), 6.88 (1H, d, J=8.8 Hz), 6.74 (1H,dd, J=8.8, 1.5 Hz), 6.51 (1H, d, J=1.5 Hz), 3.72 and 3.40 (each 3H, s)

Mass m/e (FD): 439 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.22 H.sub.21 N.sub.3 O.sub.5 S                                C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.13       4.82   9.56                                          found (%)    60.13       4.77   9.50                                          ______________________________________                                    

EXAMPLE 98N-(Thiazolyl)-4-{N-[(E)-3-(3,4-dimethoxyphenyl)-2-propenoyl]amino}benzenesulfonamide##STR236##

m.p. (°C.): 256˜258 (CH₂ Cl₂)

¹ H-NMR (90 MHz, DMSO-d₆) δ: 7.79 (4H, s), 7.57 (1H, d, J=15.6 Hz), 7.24(1H, d, J=4.8 Hz), 7.26˜7.05 (2H, m), 7.00 (1H, d, J=9.2 Hz), 6.81 (1H,d, J=4.8 Hz), 6.69 (1H, d, J=15.6 Hz), 3.82 and 3.80 (each 13H, s)

Mass m/e (FD): 445 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.20 H.sub.19 N.sub.3 O.sub.5 S.sub.2.0.25H.sub.    2 O                                                                                      C         H      N                                                 ______________________________________                                        calculated (%)                                                                             53.38       4.37   9.34                                          found (%)    53.55       4.37   9.08                                          ______________________________________                                    

EXAMPLE 994-{N-[(E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoyl]amino}benzenesulfonamid##STR237##

m.p. (°C.): 242˜243 (EtOH)

¹ H-NMR (400 MHz, DMSO-d₆) δ: 10.38 (1H, s), 9.53 (1H, s), 7.80 (2H, d,J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 7.49 (1H, d, J=15.9 Hz), 7.20 (2H,s), 7.16 (1H, s), 7.04 (1H, d, J=8.1 Hz), 6.79 (1H, d, J=8.1 Hz), 6.61(1H, d, J=15.9 Hz), 3.79 (3H, s)

Mass m/e (FD): 348 (M⁺)

    ______________________________________                                        elemental analysis as C.sub.16 H.sub.16 N.sub.2 O.sub.5 S.0.3H.sub.2 O                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             54.43       4.69   7.92                                          found (%)    54.42       5.00   7.56                                          ______________________________________                                    

We claim:
 1. A pharmaceutical composition which comprises an effectivephospholipase A₂ inhibiting amount of a benzenesulfonamide derivativerepresented by the general formula: ##STR238## wherein R¹ stands for ahydrogen atom, a cyano, nitro or hydroxy group, a halogen atom, a loweralkoxy group, an acyloxy group wherein said acyl moiety is a residue ofan organic saturated or unsaturated aliphatic, carbocyclic or heteroarylcarboxylic acid wherein the hetero atom is oxygen, nitrogen or sulfur,--SO₂ --R⁸ wherein R⁸ stands for a lower alkyl group, a heteroarylwherein the hetero atom is a nitrogen, oxygen or sulfur atom, aglycyloxy group, or a group represented by the formula: ##STR239##wherein p is an integer of 1 to 3; n is an integer of 1 to 4;R² standsfor a hydrogen atom or a pyridyl group; R³ stands for a hydrogen atom ora lower alkyl, cyano or pyridyl group; R⁴ stands for a hydrogen atom ora lower alkyl group; R⁵ stands for a hydrogen atom, a lower alkyl group,a group represented by the formula: --(CH₂)_(q) --A wherein q is aninteger of 1 to 4, and A stands for a hydroxyl group, a grouprepresented by the formula: ##STR240## wherein R⁹ and R¹⁰ may be thesame or different and each stand for a hydrogen atom or a lower alkylgroup, and R⁶ stands for a group represented by the formula: ##STR241##wherein R¹¹ stands for a hydrogen atom or a lower alkyl group or a grouprepresented by the formula: ##STR242## wherein s is an integer of 2 to 5and q is an integer of 1 to 4, an azabicycloalkyl group which is abicycloalkyl group in which one carbon atom is replaced by a nitrogenatom, or a group represented by the formula: ##STR243## wherein g and hare each an integer of 1 to 4, and B stands for a lower alkyl group, anarylalkyl group, an arylalkyl group substituted by lower alkyl, halogenor a lower alkoxy group, or a pyridylalkyl group, or a pyridylalkylgroup substituted with a lower alkyl group, a halogen or a lower alkoxygroup, or, R⁵ or R⁶ are the same or different from each other and eachstands for a group represented by the formula: ##STR244## wherein R¹¹stands for a hydrogen atom or a lower alkyl group or a group representedby the formula: ##STR245## wherein s is an integer of 2 to 5 and q is aninteger of 1 to 4, an azabicycloalkyl group which is a bicycloalkylgroup in which one carbon atom is replaced by a nitrogen atom, or agroup represented by the formula: ##STR246## wherein g and h are each aninteger of 1 to 4, and B stands for a lower alkyl group, an arylalkylgroup, an arylalkyl group substituted by lower alkyl, halogen or a loweralkoxy group, or a pyridylalkyl group, or a pyridylalkyl groupsubstituted with a lower alkyl group, a halogen or a lower alkoxy group,or R⁵ and R⁶ may be combined together to form a 6- or 7-membered ringwhich may contain a nitrogen or oxygen atom in addition to the nitrogenatom to which R⁵ and R⁶ are bonded, and said 6- or 7-membered ring maybe substituted with a lower alkyl, arylalkyl, cycloalkylalkyl orheteroarylalkyl group; a plurality of R⁷ groups each independently standfor a hydrogen atom, a lower alkyl group, a lower alkoxy group or ahalogen atom; and r is an integer of 1 to 2, provided that when r is 2,the two R⁷ groups may form a cyclohexenyl or phenyl ring together withtwo adjacent carbon atoms constituting the benzene ring; and m is aninteger of 1 to 2; or a pharmacologically acceptable salt thereof; and apharmaceutically acceptable carrier.
 2. The composition as set forth inclaim 1, wherein R¹ is a group represented by the formula: --SO₂ --R⁸(wherein R⁸ stands for a lower alkyl group), an imidazolyl, cyano ornitro group, a halogen or hydrogen atom or a hydroxyl group.
 3. Thecomposition as set forth in claim 1, wherein R¹ is a group representedby the formula: --SO₂ CH₃.
 4. The composition as set forth in claim 1,wherein R¹ is a --SO₂ CH₃ group, n is 1 and the --SO₂ CH₃ group ispresent at the p-position.
 5. The composition as set forth in any ofclaims 1, 2, 3 or 4, wherein R² and R³ are each a hydrogen atom and mis
 1. 6. The composition as set forth in any of claims 1, 2, 3 or 4,wherein R⁴ is a methyl group.
 7. The composition as set forth in any ofclaims 1, 2, 3 or 4, wherein R⁴ is an isopropyl.
 8. The composition asset forth in any of claims 1, 2, 3 or 4, wherein R⁷ is a hydrogen atom.9. The composition as set forth in any of claims 1, 2, 3 or 4, whereinR⁵ and R⁶ is a group represented by the formula: ##STR247## (wherein gand h are each an integer of 1 to 4; and B stands for a lower alkylgroup, a substituted or unsubstituted arylalkyl group or a substitutedor unsubstituted pyridylalkyl group).
 10. The composition as set forthin any of claims 1, 2, 3 or 4, wherein R⁵ and R⁶ are combined togetherto form a 6- or 7-membered ring which may contain a nitrogen or oxygenatom in addition to the nitrogen atom to which R⁵ and R⁶ are bonded andwhich may be substituted with a lower alkyl, arylalkyl, cycloalkylalkylor heteroarylalkyl group.
 11. The composition as set forth in any ofclaims 1, 2, 3 or 4, wherein R⁵ and R⁶ is a group represented by theformula: ##STR248## wherein q is an integer of 1 to 4 and R¹¹ stands fora hydrogen atom or a lower alkyl group.
 12. The composition as set forthin claim 1, wherein the derivative isN-(1-benzyl-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl-2-propenoyl]amino}benzenesulfonamide.13. The composition as set forth in claim 1, wherein the derivative isN-[1-(2-phenylethyl)-4-piperidyl-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide.14. The composition as set forth in claim 1, wherein the derivative isN-[2-(6-methyl-2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide.15. The composition as set forth in claim 1, wherein the derivative is acompound selected from a group consistingof:N-methyl-N-[2-(6-methyl-2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,E-N-methyl-N-{4-[4-(2-phenylethyl)homopiperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide,(±)-N-[1-(2-pyridylmethyl)-3-hexamethyleneimino]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,(±)-N-[1-benzyl-3-hexamethyleneiminol-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,N-[1-(2-methylpropyl)-4-piperidyl)-4-{N-methyl-N-[{E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,N-methyl-N-[2-(2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,N-[2-(2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,(E)-N-methyl-N-[4-(4-benzyl-1-homopiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide,and(E)-N-methyl-N-{4-[4-(2-phenylethyl)piperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide.